Redlich Professor, Professor of Anesthesiology, Perioperative, and Pain Medicine and, by courtesy, of Neurology at the Stanford University Medical Center

Anesthesiology, Perioperative and Pain Medicine

Bio

Bio

Sean Mackey, M.D., Ph.D, is Chief of the Division of Pain Medicine and Redlich Professor of Anesthesiology, Perioperative and Pain Medicine, Neurosciences and Neurology at Stanford University. He is the Immediate Past President of the American Academy of Pain Medicine. Dr. Mackey received his BSE and MSE in Bioengineering from University of Pennsylvania and his PhD in Electrical and Computer Engineering as well as MD from University of Arizona. Dr. Mackey is author of over 200 journal articles, book chapters, abstracts, and popular press pieces in addition to numerous national and international lectures.

Under Dr. Mackey’s leadership, the Stanford Pain Management Center has been designated a Center of Excellence by the American Pain Society, one of only two centers to receive this honor twice. In 2011 he was a member of the Institutes of Medicine committee that issued the report on Relieving Pain in America. He is currently Co-Chair of the Oversight Committee for the NIH/Health and Human Services National Pain Strategy, an effort to establish a national health strategy for pain care, education and research.

Under Dr. Sean Mackey’s leadership, researchers at the Stanford Pain Management Center and the Stanford Systems Neuroscience and Pain Laboratory (SNAPL) have made major advances in the understanding of chronic pain as a disease in its own right, one that fundamentally alters the nervous system. Dr. Mackey has overseen efforts to map the specific brain and spinal cord regions that perceive and process pain, which has led to the development of a multidisciplinary treatment model that translates basic science research into innovative therapies to provide more effective, personalized treatments for patients with chronic pain.

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Research & Scholarship

Current Research and Scholarly Interests

Functional neuroimaging of pain. Imaging of cognitive and affective dimensions of pain, neural plasticity contributing to chronic pain and effects of treatment.

Effects of membrane stabilizing medications on neuropathic pain.

Chronic pain outcomes tools development and measurement.

Clinical Trials

Low-Dose Naltrexone for the Treatment of Complex Regional Pain SyndromeRecruiting

The investigators are testing treatment with low-dose naltrexone (LDN) for symptom relief of
complex regional pain syndrome (CRPS). Study participants will be randomly assigned to
receive either LDN or placebo for a period of several weeks. During this period participants
will be asked to come to several visits, which will include sensory testing, physical
assessments, and questionnaires.

The aim of the current study is to assess the efficacy of TMS in the treatment of Complex
Regional Pain Syndrome (CRPS). It is hypothesized that participants who receive TMS (Group 1)
relative to sham treatment (Group 2) once daily for two days will demonstrate a greater
improvement in CRPS-related pain and other associated symptomology (i.e., cognitive,
emotional and physical) compared to baseline. Participants will be followed until they reach
their baseline for two consecutive weeks to assess safety and duration of symptom
alleviation.

This study aims to compare the efficacy of a single session psychological treatment, "From
Catastrophizing to Recovery" (FCR), with the current standard of care, group Cognitive
Behavioral Therapy (CBT) specifically on individuals with chronic low back pain suffering
from Pain Catastrophizing (PC).

The purpose of the Stanford Center for Back Pain is to investigate and characterize the
mechanisms of four treatments for chronic low back pain. These interventions (research
treatment) include real-time fMRI neurofeedback, mindfulness based stress reduction,
cognitive behavioral therapy, and acupuncture treatment. The investigators plan to
characterize both mechanisms of treatment effects and efficacy.

The purpose of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy
for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) Trial is to confirm
the safety and effectiveness of the MitraClip System for the treatment of moderate-to-severe
or severe functional mitral regurgitation (FMR) in Symptomatic Heart Failure Subjects who are
treated per standard of care and who have been determined by the site's local heart team as
not appropriate for mitral valve surgery. This randomized controlled trial will provide the
opportunity to strengthen or add labeling claims regarding safety and clinical benefits of
the MitraClip System for symptomatic heart failure patients with moderate-to-severe or severe
functional mitral regurgitation.
Approximately 610 subjects will be randomized at up to 100 investigational sites with
approximately 305 subjects targeted to receive the study device. COAPT study completed
recruiting subjects in June 2017.
As part of the COAPT trial, a subset of patients will be registered in the cardiopulmonary
exercise (CPX) sub-study. The objective of this sub-study is to evaluate the exercise
responses in a sub-cohort of COAPT subjects who receive MitraClip device (Device group)
compared to the Control group who do not receive MitraClip device. (Note: the CPX Sub-study
subjects will contribute to the analyses of the COAPT primary and secondary endpoints)
As an extension of the COAPT RCT trial, COAPT CAS study will be conducted after COAPT
enrollment is complete under the same investigational device exemption (IDE(G120024)). The
objective of this study is to evaluate the MitraClip® NT System for the treatment of
clinically significant functional mitral regurgitation (FMR) in symptomatic heart failure
subjects who are treated per standard of care and who have been determined by the site's
local heart team as not appropriate for mitral valve surgery. The anticipated study Primary
Completion date is July 2018 and the Study Completion Date is July 2024. COAPT CAS is
presently recruiting subjects.

Lumbar sympathetic blocks are part of the standard of care for treating patients with
sympathetically-maintained pain (e.g. in complex regional pain syndrome or reflex sympathetic
dystrophy- RSD). In these patients lower extremity pain can be reduced or abolished
temporarily by blocking sympathetic nerves by doing a lumbar sympathetic block. Patients who
respond only transiently to sympathetic blocks often choose between potentially dangerous
lumbar sympathetic block with neurolytic agents, surgical sympathectomy, continued severe
refractory debilitating pain or other risky invasive surgical procedures such as spinal cord
electrical stimulation.. It is hypothesized that Botulinum Toxin Type A (BTA) injected in a
lumbar sympathetic block can provide extended sympathetic blockade and thus pain relief. This
pilot study aims to see if BTA can be used safely in lower extremity sympathetic blocks, and
might be useful in providing prolonged pain relief.

Stanford is currently not accepting patients for this trial.For more information, please contact Ian Carroll, (650) 498 - 6885.

Superficial injection of Botulinum toxin has been advocated for cosmetic purposes but has
also been reported to be helpful for some pain conditions. The investigators have observed
prolonged profound analgesia following subcutaneous superficial injection of Botulinum Toxin
Type A (BTA) in patients with certain types of neuropathic pain. The investigators propose to
study if addition of BTA extends pain relief compared to placebo when injected subcutaneously
into areas of cutaneous allodynia (the property that a normally non-noxious stimulus is
perceived as painful).

Stanford is currently not accepting patients for this trial.For more information, please contact Rachel Moericke, (650) 724 - 0522.

Determine if T3 - the active form of thyroid hormone - is beneficial in fibromyalgia.
Determine the feasibility and promise of an appropriately powered future prospective
randomized controlled study of using T3 (the active form of thyroid hormone) for the
treatment of fibromyalgia. We specifically aim to assess the feasibility, cost, obstacles and
promise of conducting a prospective controlled study in the future.

Stanford is currently not accepting patients for this trial.For more information, please contact Rebecca McCue, (650) 724 - 0522.

Our goals for this study involve using intravenous lidocaine as it is normally used in the
Stanford Pain Management Center to assess the effect of intravenous lidocaine on chronic
pain. Studies have been done determining the efficacy of intravenous lidocaine for treating
pain but little research has been done to determine the effects of an intravenous lidocaine
infusion on the different components of the pain experience. Our study will incorporate pain
quality measures both before and during the infusions of lidocaine to determine changes in
present pain intensity.

Superficial injection of Botulinum toxin has been advocated for cosmetic purposes but has
also been reported to be helpful for some pain conditions. The investigators have observed
prolonged profound analgesia following subcutaneous superficial injection of Botulinum Toxin
Type A (BTA) in patients with certain types of neuropathic pain. the investigators propose to
study if addition of BTA extends pain relief compared to placebo when injected subcutaneously
into areas of cutaneous allodynia (the property that a normally non-noxious stimulus is
perceived as painful).

Stanford is currently not accepting patients for this trial.For more information, please contact Charlie Wang, (650) 723 - 8250.

The goal of this study is to determine whether administering Gabapentin prior to surgery
affects duration of pain and opioid use post-surgery. The investigators aim to compare
gabapentin to placebo in a prospective, randomized clinical trial in which patients will be
followed post-surgery until pain resolves and opioid use ceases.

Stanford is currently not accepting patients for this trial.For more information, please contact Debra Clay, 650-724-1753.

The purpose of this study is to determine whether compassion training will improve the
physical and psychological well-being of patients with chronic pain. The investigators also
want to determine whether any benefit of compassion training in the patients "spreads" to
significant others with whom the patient has a close relationship.

Stanford is currently not accepting patients for this trial.For more information, please contact Heather Chapin, PhD, 650-723-3032.

Low Dose Naltrexone (LDN) has been reported anecdotally to reduce the symptoms of
Fibromyalgia, a Chronic Multisystem Illness. The drug may work by regulating natural
pain-reducing systems. In this study, we will administer both LDN and placebo to a small
group of individuals with Fibromyalgia and Gulf War Syndrome, both Chronic Multisymptom
Illnesses, to assess the drug's efficacy in treating the condition.

We hope to determine whether Ondansetron, an anti-nausea medication, works to help relieve
withdrawal symptoms experienced while the patient is being weaned off opioid medications.
This medication has shown anecdotal evidence of being affective for the treatment of
withdrawal symptoms and we hope to determine whether this is affective.

Stanford is currently not accepting patients for this trial.For more information, please contact Rebecca McCue, (650) 724 - 0522.

Duloxetine has recently been shown to be effective in reducing the pain in chronic pain
patients. Duloxetine is known to exert a central mechanism, however the precise human brain
structures responsible for mediating its pain-relieving properties are not known. We will use
functional magnetic resonance imaging (FMRI) to investigate the neural and functional
correlates of pain.

Stanford is currently not accepting patients for this trial.For more information, please contact Neil Chatterjee, (650) 724 - 0522.

Abstract

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality.METHODS: The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given.RESULTS: Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100mg, 1.2mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities.CONCLUSIONS: Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.

Abstract

BACKGROUND: Chronic low back pain (CLBP) is the most common chronic pain condition and is often resistant to conventional treatments. Acupuncture is a popular alternative for treating CLBP but its mechanisms of action remain poorly understood. Evidence suggests that pain regulatory mechanisms (particularly the ascending and secondarily the descending pain modulatory pathways) and psychological mechanisms (e.g., expectations, pain catastrophizing and self-efficacy) may be involved in the pathogenesis of CLBP and its response to treatments. We will examine these mechanisms in the treatment of CLBP by electroacupuncture (EA).METHODS: We present the aims and methods of a placebo-controlled, participant-blinded and assessor-blinded mechanistic study. Adult patients with CLBP will be randomized to receiving 16 sessions of real (active) or sham (placebo) EA over the course of 8weeks. The primary pain regulatory measure for which the study was powered is temporal summation (TS), which approximates ascending pain facilitation. Conditioned pain modulation (CPM), representing a descending pain modulatory pathway, will be our secondary pain regulatory measure. The primary psychological measure is expectations of benefit, and the secondary psychological measures are pain catastrophizing and self-efficacy in managing pain. Main clinical outcomes are back pain bothersomeness on a 0-100 visual analog scale (primary), Roland Morris Disability Questionnaire (secondary), and relevant items from the National Institutes of Health (NIH) Patient-Reported Outcome Measures Information System (secondary). We hypothesize that compared to sham, real EA will lead to greater reduction in TS after 8 treatment sessions (4weeks); and that reduction in TS (and secondarily, increase in CPM) after 8 treatment sessions will mediate reduction in back pain bothersomeness from baseline to week 10 (clinical response) to EA. We also hypothesize that the three psychological factors are moderators of clinical response. With 100 treatment completers, the study is designed to have 80% power to detect a medium-sized between-group effect (d=0.5) on temporal summation.DISCUSSION: To the best of our knowledge, this is the first appropriately powered, placebo-controlled clinical trial evaluating mechanisms of EA in the treatment of CLBP.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02503475 . Registered on 15 July 15 2015. Retrospectively registered.

Abstract

Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the cortico-striatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and 11C-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and 11C-raclopride PET. We estimated raclopride binding potential (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.

Abstract

INTRODUCTION: Patient-reported outcomes are important for clinical research and will likely be used in the near future as a metric for physician reimbursement. This study aims to evaluate the implementation of an electronic data collection system for deep vein thrombosis and lymphedema quality-of-life (QOL) questionnaires in a tertiary care interventional radiology practice.METHODS: A single provider's clinic patients were automatically e-mailed validated questionnaires 1 week before their appointments. If not completed via e-mail, the questionnaire was administered on an electronic tablet in clinic by a research coordinator. Patients were also sent postprocedure questionnaires.RESULTS: In all, 106 patients visited the clinic for a pre-intervention venous consultation. Of them, 96% (n= 102 of 106) completed the pre-intervention questionnaire: 48% (n= 47 of 98) via e-mail and 52% (n= 51 of 98) via tablet. Of the patients who had procedures and were sent questionnaires, 49% (n= 26 of 53) were seen in person. Of the postprocedure in-person clinic patients, 76% (n= 20 of 26) completed the questionnaire via e-mail, and the remainder with the tablet in clinic. Twenty-seven of the 53 (51%) patients did not return for follow-up and instead were sent an electronic questionnaire as their only source of follow-up, of which 74% (n= 20 of 27) complied.CONCLUSION: After an initial introduction to electronic QOL reporting, patients were more likely to complete the questionnaires remotely for their follow-up appointment. A semi-automated electronic QOL system allows physicians to collect patient outcome data even in the absence of a clinic visit.

Abstract

PURPOSE: Simultaneous brain and spinal cord functional MRI is emerging as a new tool to study the central nervous system but is challenging. Poor B0 homogeneity and small size of the spinal cord are principal obstacles to this nascent technology. Here we extend a dynamic shimming approach, first posed by Finsterbusch, by shimming per slice for both the brain and spinal cord.METHODS: We shim dynamically by a simple and fast optimization of linear field gradients and frequency offset separately for each slice in order to minimize off-resonance for both the brain and spinal cord. Simultaneous acquisition of brain and spinal cord fMRI is achieved with high spatial resolution in the spinal cord by means of an echo-planar RF pulse for reduced FOV. Brain slice acquisition is full FOV.RESULTS: T2*-weighted images of brain and spinal cord are acquired with high clarity and minimal observable image artifacts. Fist-clenching fMRI experiments reveal task-consistent activation in motor cortices, cerebellum, and C6-T1 spinal segments.CONCLUSIONS: High quality functional results are obtained for a sensory-motor task. Consistent activation in both the brain and spinal cord is observed at individual levels, not only at group level. Because reduced FOV excitation is applicable to any spinal cord section, future continuation of these methods holds great potential.

Abstract

Chronic pain, one of the most common reasons adults seek medical care (1), has been linked to restrictions in mobility and daily activities (2,3), dependence on opioids (4), anxiety and depression (2), and poor perceived health or reduced quality of life (2,3). Population-based estimates of chronic pain among U.S. adults range from 11% to 40% (5), with considerable population subgroup variation. As a result, the 2016 National Pain Strategy called for more precise prevalence estimates of chronic pain and high-impact chronic pain (i.e., chronic pain that frequently limits life or work activities) to reliably establish the prevalence of chronic pain and aid in the development and implementation of population-wide pain interventions (5). National estimates of high-impact chronic pain can help differentiate persons with limitations in major life domains, including work, social, recreational, and self-care activities from those who maintain normal life activities despite chronic pain, providing a better understanding of the population in need of pain services. To estimate the prevalence of chronic pain and high-impact chronic pain in the United States, CDC analyzed 2016 National Health Interview Survey (NHIS) data. An estimated 20.4% (50.0 million) of U.S. adults had chronic pain and 8.0% of U.S. adults (19.6 million) had high-impact chronic pain, with higher prevalences of both chronic pain and high-impact chronic pain reported among women, older adults, previously but not currently employed adults, adults living in poverty, adults with public health insurance, and rural residents. These findings could be used to target pain management interventions.

Abstract

Introduction: Unsafe opioid prescribing practices to treat acute and chronic pain continue to contribute to the opioid overdose crisis in the United States, a growing public health emergency that harms patients and their communities. Poor opioid prescribing practices stem in part from a lack of education and skills training surrounding pain and opioid management.Methods: As part of the Clinical Pain Medicine Fellowship at Stanford University, physicians were given the opportunity to participate in a pilot program to practice opioid management in a live, simulated interaction. Twenty-seven physician trainees participated in the simulation with a live, standardized patient actor. Before beginning the simulation, participants were given a detailed patient history that included the patient's risk for opioid abuse. They were also provided with relevant risk evaluation and mitigation (REM) tools. All simulation interactions were video-recorded and coded by two independent reviewers. A detailed coding scheme was developed before video analysis, and an inter-rater reliability score showed substantial agreement between reviewers.Results: Contrary to expectations, many of the observed performances by trainees contained aspects of unsafe opioid prescribing, given the patient history. Many trainees did not discuss their patient's aberrant behaviors related to opioids or the patient's risk for opioid abuse. Marked disparities were also observed between the trainees' active patient interactions and their written progress notes.Discussion: This simulation addresses a pressing need to further educate, train, and provide point-of-care tools for providers prescribing opioids. We present our experience and preliminary findings.

Abstract

Fibromyalgia is a multifaceted chronic pain condition of unknown etiology. Conditioned pain modulation (CPM) such as cold water pressor test of the foot, is widely documented as being disrupted in patients with fibromyalgia. To date, the mechanisms underlying such dysregulation of the descending control of pain in fibromyalgia remain poorly understood. In this study, we used ICA-based network analysis to comprehensively compare differences in functional network connectivity among relevant (nonartifactual) intrinsic connectivity brain networks during the resting state before and after cold pressor test in patients with fibromyalgia and healthy controls. The results revealed significant differences in functional connectivity between the two groups that included the networks that integrate cognitive control and attention systems with memory, emotion and brainstem regions. Specifically, functional connectivity involving central executive network was absent in patients with fibromyalgia compared with controls. Patients showed significant functional connectivity changes involving subcortical and brainstem networks with the sensorimotor and dorsal attention networks. Accordingly, aberrant CPM in patients with fibromyalgia may be due to the differences in functional connectivity involving the subcortical/brainstem regions, and is facilitated by the recruitment of the dorsal attention network in lieu of the central executive network. Future research replicating the present findings with larger sample size can shed more light on neurobiology of endogenous pain modulation in fibromyalgia.

Abstract

Motion-induced artifact detection has become a fixture in the assessment of functional magnetic resonance imaging (fMRI) quality control. However, the effects of other MR image quality (IQ) metrics on intrinsic connectivity brain networks are largely unexplored. Accordingly, we report herein the initial assessment of the effects of a comprehensive list of IQ metrics on resting state networks using a multivariate analysis of covariance (MANCOVA) approach based on high-order spatial independent component analysis (ICA). Three categories of MR IQ metrics were considered: (1) metrics for artifacts including the AFNI outlier ratio and quality index, framewise displacement, and ghost to signal ratio, (2) metrics for the temporal quality of MRI data including the temporal framewise change in global BOLD signals (DVARS), global correlation of time-series, and temporal signal to noise ratio, (3) metrics for the structural quality of MRI data including the entropy focus criterion, foreground-background energy ratio, full-width half maximum smoothness, and static signal to noise ratio. After FDR-correction for multiple comparisons, results showed significant effects of the static and temporal signal to noise ratios on the spatial map intensities of the basal ganglia, default-mode and cerebellar networks. AFNI outlier ratio, framewise displacement and DVARS exhibited significant effects on the BOLD power spectra of sensorimotor networks. The global correlation of time-series displayed wide-spread modulation of the spectral power in most networks. Further investigations of the effect of IQ metrics on the characteristics of intrinsic connectivity brain networks allow more accurate interpretation of the fMRI results.

Abstract

Physiological noise corrections using RETROICOR algorithm has been shown to increase signal sensitivity in resting state networks such as the default-mode network. However, independent component analysis (ICA)-based network approach may suffer from such corrections especially if there is any overlap between two sources in the decomposition domain. To address the extent the physiological noise corrections may impact ICA derived intrinsic connectivity brain networks, we measured network features including functional network connectivity (FNC), power spectra, and network spatial maps in the resting state and task functional magnetic resonance imaging (fMRI) data that were acquired in the same visit from a group of healthy volunteers. Statistical analysis showed functional connectivity between several networks were significantly changed after RETROICOR corrections in both rest and task fMRI. Significant FNC alterations were found in the subcortical, basal ganglia, salience, and default-mode networks. Power spectra analysis showed a trend toward lower power spectra in the subcortical and salience networks at [0.20 and 0.24] Hz after RETROICOR corrections in both rest and task fMRI. Furthermore, physiological noise corrections led to volumetric decrease in the resting state networks that included the subcortical, basal ganglia, salience, and default-mode networks, and volumetric enlargement in the sensorimotor and cerebellar networks. In task fMRI data, physiological noise corrections generally resulted in the expansion of networks except for task-activated networks including the anterior salience, central executive, dorsal attention, and cerebellar networks. If confirmed with larger sample sizes, these results suggest that physiological noise corrections alter some network features, and that such alterations are different between resting state and task fMRI data.

Abstract

Neuroimaging research has demonstrated definitive involvement of the central nervous system in the development, maintenance, and experience of chronic pain. Structural and functional neuroimaging has helped elucidate central nervous system contributors to chronic pain in humans. Neuroimaging of pain has provided a tool for increasing our understanding of how pharmacologic and psychologic therapies improve chronic pain. To date, findings from neuroimaging pain research have benefitted clinical practice by providing clinicians with an educational framework to discuss the biopsychosocial nature of pain with patients. Future advances in neuroimaging-based therapeutics (e.g., transcranial magnetic stimulation, real-time functional magnetic resonance imaging neurofeedback) may provide additional benefits for clinical practice. In the future, with standardization and validation, brain imaging could provide objective biomarkers of chronic pain, and guide treatment for personalized pain management. Similarly, brain-based biomarkers may provide an additional predictor of perioperative prognoses.

Abstract

Although many factors have been proposed to trigger symptom exacerbations (flares) in patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, few studies have investigated these factors empirically. Therefore, we embedded a case-crossover study in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain longitudinal study to evaluate a range of patient reported triggers.We assessed exposure to proposed triggers, including diet, physical activities, sedentary behaviors, stress, sexual activities, infection-like symptoms and allergies, by questionnaire a maximum of 3 times when participants reported flares and at 3 randomly selected times. We compared participant preflare to nonflare exposures by conditional logistic regression.In our full analytical sample of 292 participants only 2 factors, including recent sexual activity (OR 1.44, 95% CI 1.06-1.96) and urinary tract infection symptoms (OR 3.39, 95% CI 2.02-5.68), which may overlap with those of flares, were associated with flare onset. On subanalyses restricted to flares with specific suspected triggers additional positive associations were observed for some factors such as certain dietary factors, abdominal muscle exercises, and vaginal infection-like symptoms and fever, but not for other factors (eg stress).Except for sexual activity our findings suggest that patient reported triggers may be individual or group specific, or they may not contribute to flares. These findings suggest caution in following rigid, global flare prevention strategies and support additional research to develop evidence-based strategies.

Abstract

Background: Evidence suggests social interactions play an important role in pain perception.Purpose: The aim of this study was to determine whether social isolation (SI) in people with persistent pain determines pain interference (PI) and physical function over time.Methods: Patients seeking care at a tertiary pain management referral center were administered the Patient Reported Outcome Measurement Information System (PROMIS) SI, PI, physical function, depression, and average pain intensity item banks at their initial consultation and subsequent visits as part of their routine clinical care. We used a post hoc simulation of an experiment using propensity score matching (n = 4,950) and carried out a cross-lagged longitudinal analysis (n = 312) of retrospective observational data.Results: Cross-lagged longitudinal analysis showed that SI predicted PI at the next time point, above and beyond the effects of pain intensity and covariates, but not vice versa.Conclusions: These data support the importance of SI as a factor in pain-related appraisal and coping and demonstrate that a comprehensive assessment of the individuals' social context can provide a better understanding of the differential trajectories for a person living with pain. Our study provides evidence that the impact of pain is reduced in individuals who perceive a greater sense of inclusion from and engagement with others. This study enhances the understanding of how social factors affect pain and have implications for how the effectiveness of therapeutic interventions may be improved. Therapeutic interventions aimed at increasing social connection hold merit in reducing the impact of pain on engagement with activities.

Abstract

A key component to chronic pain management regimens is the use of analgesic medications. Psychological factors, such as mood states, may also affect the use of pain medications for individuals with chronic pain, but few observational studies have examined how these factors may predict pain medication use at the daily level.Daily assessments from 104 individuals with back pain were used to examine fluctuations in daily pain intensity, mood, sleep quality, and physical activity as predictors of the likelihood of pain medication (opioid and non-opioid) use and levels of medication use on the same day.Pain intensity and mood ratings significantly predicted whether participants used pain medication on the same day, while only pain intensity predicted whether participants used more medication than usual. Further, current opioid users were more likely to increase the amount of their medication use on days of higher pain.This article identifies fluctuations in daily pain intensity and mood as salient predictors of daily pain medication use in individuals with recurrent back pain. The current study is among the first to highlight both pain and mood states as predictors of daily pain medication use in individuals with back pain, though future studies may expand on these findings through the use of higher-resolution daily medication use variables.

Abstract

Perceived injustice (PI) has been identified as an important risk factor for pain-related outcomes. To date, research has shown that pain acceptance and anger are mediators of the association between PI and pain-related outcomes. However, a combined conceptual model that addresses the interrelationships between these variables is currently lacking. Therefore, the current study aimed to examine the potential mediating roles of pain acceptance and anger on the association between PI and adverse pain-related outcomes (physical function, pain intensity, opioid use status).This cross-sectional study used a sample of 354 patients with chronic pain being treated at a tertiary pain treatment center. Participants completed measures of PI, pain acceptance, anger, physical function, pain intensity, and opioid use status. Mediation analyses were used to examine the impact of pain acceptance and anger on the association between PI and pain-related outcomes.Examination of the specific indirect effects revealed that pain acceptance fully mediated the relationship between PI and physical function, as well as the relationship between PI and opioid use status. Pain acceptance emerged as a partial mediator of the relationship between PI and pain intensity.This is the first study to provide a combined conceptual model investigating the mediating roles of pain acceptance and anger on the relationship between PI and pain outcomes. On the basis of our findings, low levels of pain acceptance associated with PI may help explain the association between PI and adverse pain outcomes. Clinical and theoretical implications are discussed.

Abstract

"The ongoing opioid crisis lies at the intersection of two substantial public health challenges-reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications" [1]. Improved pain education for health care providers is an essential component of the multidimensional response to both still-unmet challenges [2,3]. Despite the importance of licensing examinations in assuring competency in health care providers, there has been no prior appraisal of pain and related content within the United States Medical Licensing Examination (USMLE).An expert panel developed a novel methodology for characterizing USMLE questions based on pain core competencies and topical and public health relevance.Under secure conditions, raters used this methodology to score 1,506 questions, with 28.7% (432) identified as including the word "pain." Of these, 232 questions (15.4% of the 1,506 USMLE questions reviewed) were assessed as being fully or partially related to pain, rather than just mentioning pain but not testing knowledge of its mechanisms and their implications for treatment. The large majority of questions related to pain (88%) focused on assessment rather than safe and effective pain management, or the context of pain.This emphasis on assessment misses other important aspects of safe and effective pain management, including those specific to opioid safety. Our findings inform ways to improve the long-term education of our medical and other graduates, thereby improving the health care of the populations they serve.

Abstract

The Institute of Medicine (IOM) reported that chronic pain affects about 100 million U.S. adults, with chronic low back pain (CLBP) cited as the most prevalent type. Pain catastrophizing is a psychological construct shown to predict the development and trajectory of chronic pain and patient response to pain treatments. While effective treatment for pain catastrophizing typically includes eight-session groups of cognitive behavioral therapy (CBT), a single-session targeted treatment class yielded promising results which, if replicated and extended, could prove to efficiently and cost-effectively reduce pain catastrophizing. In this trial, we seek to determine the comparative efficacy of this novel single-session pain catastrophizing class to an eight-session course of pain CBT and a single-session back pain health education class. We will also explore the psychosocial mechanisms and outcomes of pain catastrophizing treatment.In this trial we will randomize 231 individuals with CLBP to one of three treatment arms: (1) pain-CBT (eight weekly 2-h group sessions with home exercises and readings); (2) a single 2-h pain catastrophizing class; or (3) a single 2-h back pain health education class (active control). For the primary outcome of pain catastrophizing, the trial is designed as a non-inferiority test between pain-CBT and the single-session pain catastrophizing class, and as a superiority test between the single-session pain catastrophizing class and the health education class. Team researchers masked to treatment assignment will assess outcomes up to six months post treatment.If the single-session targeted pain catastrophizing class is found to be an effective treatment for patients with CLBP, this low cost and low burden treatment could dismantle many of the current barriers and burdens of effective pain care. Further, elucidation of the mechanisms of pain catastrophizing treatments will facilitate future research on the topic as well as further development and refinement of treatments.ClinicalTrials.gov, NCT03167086 . Registered on 22 May 2017.

Abstract

Chronic pain symptoms often change over time, even in individuals who have had symptoms for years. Studying biological factors that predict trends in symptom change in chronic pain may uncover novel pathophysiological mechanisms and potential therapeutic targets. In this study, we investigated whether brain functional connectivity measures obtained from resting-state functional magnetic resonance imaging at baseline can predict longitudinal symptom change (3, 6, and 12 months after scan) in urologic chronic pelvic pain syndrome. We studied 52 individuals with urologic chronic pelvic pain syndrome (34 women, 18 men) who had baseline neuroimaging followed by symptom tracking every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We found that brain functional connectivity can make a significant prediction of short-term (3 month) pain reduction with 73.1% accuracy (69.2% sensitivity and 75.0% precision). In addition, we found that the brain regions with greatest contribution to the classification were preferentially aligned with the left frontoparietal network. Resting-state functional magnetic resonance imaging measures seemed to be less informative about 6- or 12-month symptom change. Our study provides the first evidence that future trends in symptom change in patients in a state of chronic pain may be linked to functional connectivity within specific brain networks.

Abstract

To date, there is no validated measure for pain catastrophizing at the daily level. The Pain Catastrophizing Scale (PCS) is widely used to measure trait pain catastrophizing. We sought to develop and validate a brief, daily version of the PCS for use in daily diary studies to facilitate research on mechanisms of catastrophizing treatment, individual differences in self-regulation, and to reveal the nuanced relationships between catastrophizing, correlates, and pain outcomes. After adapting the PCS for daily use, we evaluated the resulting 14 items using 3 rounds of cognitive interviews with 30 adults with chronic pain. We refined and tested the final daily PCS in 3 independent, prospective, cross-sectional, observational validation studies conducted in a combined total of 519 adults with chronic pain who completed online measures daily for 14 consecutive days. For study 1 (N = 131), exploratory factor analysis revealed adequate fit and-unexpectedly-unidimensionality for item responses to the daily PCS. Study 2 (N = 177) correlations indicated adequate association with related constructs (anger, anxiety, pain intensity, depression). Similarly, results for study 3 (N = 211) revealed expected correlations for daily PCS and measures of daily constructs including physical activity, sleep, energy level, and positive affect. Results from complex/multilevel confirmatory factor analysis confirmed good fit to a unidimensional model. Scores on the daily PCS were statistically comparable with and more parsimonious than the full 14-item version. Next steps include evaluation of score validity in populations with medical diagnoses, greater demographic diversity, and in patients with acute pain.This article describes the development and validation of a daily PCS. This daily measure may facilitate research that aims to characterize pain mechanisms, individual differences in self-regulation, adaptation, and nuanced relationships between catastrophizing, correlates, and pain outcomes.

Abstract

With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (eg, pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain.Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM).As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions.The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms.Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions.

Abstract

Objectives To identify trends in concurrent use of a benzodiazepine and an opioid and to identify the impact of these trends on admissions to hospital and emergency room visits for opioid overdose.Design Retrospective analysis of claims data, 2001-13.Setting Administrative health claims database.Participants 315 428 privately insured people aged 18-64 who were continuously enrolled in a health plan with medical and pharmacy benefits during the study period and who also filled at least one prescription for an opioid.Interventions Concurrent benzodiazepine/opioid use, defined as an overlap of at least one day in the time periods covered by prescriptions for each drug. Main outcome measures Annual percentage of opioid users with concurrent benzodiazepine use; annual incidence of visits to emergency room and inpatient admissions for opioid overdose.Results 9% of opioid users also used a benzodiazepine in 2001, increasing to 17% in 2013 (80% relative increase). This increase was driven mainly by increases among intermittent, as opposed to chronic, opioid users. Compared with opioid users who did not use benzodiazepines, concurrent use of both drugs was associated with an increased risk of an emergency room visit or inpatient admission for opioid overdose (adjusted odds ratio 2.14, 95% confidence interval 2.05 to 2.24; P<0.001) among all opioid users. The adjusted odds ratio for an emergency room visit or inpatient admission for opioid overdose was 1.42 (1.33 to 1.51; P<0.001) for intermittent opioid users and 1.81 (1.67 to 1.96; P<0.001) chronic opioid users. If this association is causal, elimination of concurrent benzodiazepine/opioid use could reduce the risk of emergency room visits related to opioid use and inpatient admissions for opioid overdose by an estimated 15% (95% confidence interval 14 to 16).Conclusions From 2001 to 2013, concurrent benzodiazepine/opioid use sharply increased in a large sample of privately insured patients in the US and significantly contributed to the overall population risk of opioid overdose.

Abstract

Minocycline is a microglial cell inhibitor and decreases pain behaviors in animal models. Minocycline might represent an intervention for reducing postoperative pain. This trial tested whether perioperative administration of minocycline reduced time to pain resolution (TPR) after standardized hand surgeries with known prolonged pain profiles: carpal tunnel release (CTR) and trigger finger release (TFR).This double-blinded randomized controlled trial included patients undergoing CTR or TFR under local anesthesia. Before surgery, participants recorded psychological and pain measures. Participants received oral minocycline, 200 mg, or placebo 2 hours prior to procedure, and then 100 mg of minocycline or placebo 2 times a day for 5 days. After surgery, participants were called daily assessing their pain. The primary end point of TPR was when participants had 3 consecutive days of 0 postsurgical pain. Futility analysis and Kaplan-Meier analyses were performed.A total of 131 participants were randomized and 56 placebo and 58 controls were analyzed. Median TPR for CTR was 3 weeks, with 15% having pain more than 6 weeks. Median TPR for TFR was 2 weeks with 18% having pain more than 6 weeks. The overall median TPR for the placebo group was 2 weeks (10% pain > 6 weeks) versus 2.5 weeks (17% pain > 6 weeks) for the minocycline group. Futility analysis found that the likelihood of a true underlying clinically meaningful reduction in TPR owing to minocycline was only 3.5%. Survival analysis found minocycline did not reduce TPR. However, subgroup analysis of those with elevated posttraumatic distress scores found the minocycline group had longer TPR.Oral administration of minocycline did not reduce TPR after minor hand surgery. There was evidence that minocycline might increase length of pain in those with increased posttraumatic stress disorder symptoms.Therapeutic I.

Abstract

A primary goal in managing pain is to reduce pain and increase physical function (PF). This goal is also tied to continuing payment for treatment services in many practice guidelines. Pain interference (PI) is often used as a proxy for measurement and reporting of PF in these guidelines. A common assumption is that reductions in PI will translate into improvement in PF over time. This assumption needs to be tested in a clinical environment. Consequently, we used the patient reported outcomes measurement information system (PROMIS) to describe the topology of the longitudinal relationship between PI in relation to PF.Longitudinal data of 389 people with chronic pain seeking healthcare demonstrated that PI partially explained the variance in PF at baseline (r = -0.50) and over 90 days of care(r = -0.65). The relationship between pain intensity and PF was not significant when PI was included as a mediator. A parallel process latent growth curve model analysis showed a weak, unidirectional relationship (β = 0.18) between average PF scores and changes in PI over the course of 90 days of care, and no relationship between average PI scores and changes in PF across time.Although PI and PF appear moderately related when measured concurrently, they do not cluster closely together across time. The differential pathways between these two domains suggest that therapies which target both the consequences of pain on relevant aspects of persons' lives, and capability to perform physical activities are likely required for restoration of a vital life.

Abstract

Pain catastrophizing, a pattern of negative cognitive-emotional responses to actual or anticipated pain, maintains chronic pain and undermines response to treatments. Currently, precisely how pain catastrophizing influences pain processing is not well understood. In experimental settings, pain catastrophizing has been associated with amplified pain processing. This study sought to clarify pain processing mechanisms via experimental induction of pain catastrophizing. Forty women with chronic low back pain were assigned in blocks to an experimental condition, either a psychologist-led 10-minute pain catastrophizing induction or a control (10-minute rest period). All participants underwent a baseline round of several quantitative sensory testing (QST) tasks, followed by the pain catastrophizing induction or the rest period, and then a second round of the same QST tasks. The catastrophizing induction appeared to increase state pain catastrophizing levels. Changes in QST pain were detected for two of the QST tasks administered, weighted pin pain and mechanical allodynia. Although there is a need to replicate our preliminary results with a larger sample, study findings suggest a potential relationship between induced pain catastrophizing and central sensitization of pain. Clarification of the mechanisms through which catastrophizing affects pain modulatory systems may yield useful clinical insights into the treatment of chronic pain.

Abstract

Recent advances in multivariate statistical analysis of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) have provided novel insights into the network organization of the human brain. Here, we applied group independent component analysis, a well-established approach for detecting brain intrinsic connectivity networks, to examine the spontaneous BOLD fluctuations in patients with fibromyalgia and healthy controls before and after exposure to a stressor. The BOLD spectral power characteristics of component time courses were calculated using the fast Fourier transform (FFT) algorithm, and group comparison was performed at six frequency bins between 0 and 0.24 Hz at 0.04 Hz intervals. Relative to controls, patients with fibromyalgia displayed significant BOLD spectral power differences in the default-mode, salience, and subcortical networks at the baseline level (PBon ferroni-corrected

Abstract

Previous research has highlighted the importance of cognitive appraisal processes in determining the nature and effectiveness of coping with chronic pain. Two of the key variables implicated in appraisal of pain are catastrophizing and perceived injustice, which exacerbate the severity of pain-related distress and increase the risk of long-term disability through maladaptive behavioural responses. However, to date, the influences of these phenomena have not been examined concurrently, nor have they been related specifically to quality of life measures, such as life satisfaction.Using data from an online survey of 330 individuals with chronic pain, structural path modelling techniques were used to examine the independent effects of pain catastrophizing, perceived injustice, and average pain intensity on life satisfaction. Two potential mediators of these relationships were examined: depressive symptoms and pain-related interference.Results indicated that depressive symptoms fully mediated the relationship between pain catastrophizing and life satisfaction, and pain interference fully mediated the relationship between pain intensity and life satisfaction. Both depressive symptoms and pain interference were found to significantly mediate the relationship between perceived injustice and life satisfaction, but perceived injustice continued to demonstrate a significant and negative relationship with life satisfaction, above and beyond the other study variables.The current findings highlight the distinct affective and behavioural mediators of pain and maladaptive cognitive appraisal processes in chronic pain, and highlight their importance in both perceptions of pain-related interference and longer-term quality of life.

Abstract

The spinal cord has an active role in the modulation and transmission of the neural signals traveling between the body and the brain. Recent advancements in functional magnetic resonance imaging (fMRI) have made the in vivo examination of spinal cord function in humans now possible. This technology has been recently extended to the investigation of resting state functional networks in the spinal cord, leading to the identification of distinct patterns of spinal cord functional connectivity. In this study, we expand on the previous work and further investigate resting state cervical spinal cord functional connectivity in healthy participants (n = 15) using high resolution imaging coupled with both seed-based functional connectivity analyses and graph theory-based metrics. Within spinal cord segment functional connectivity was present between the left and right ventral horns (bilateral motor network), left and right dorsal horns (bilateral sensory network), and the ipsilateral ventral and dorsal horns (unilateral sensory-motor network). Functional connectivity between the spinal cord segments was less apparent with the connectivity centered at the region of interest and spanning < 20 mm along the superior-inferior axis. In a subset of participants (n = 10), the cervical spinal cord functional network was demonstrated to be state-dependent as thermal stimulation of the right ventrolateral forearm resulted in significant disruption of the bilateral sensory network, increased network global efficiency, and decreased network modularity.

Abstract

Guidelines recommend using gabapentin to decrease postoperative pain and opioid use, but significant variation exists in clinical practice.To determine the effect of perioperative gabapentin on remote postoperative time to pain resolution and opioid cessation.A randomized, double-blind, placebo-controlled trial of perioperative gabapentin was conducted at a single-center, tertiary referral teaching hospital. A total of 1805 patients aged 18 to 75 years scheduled for surgery (thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, and shoulder arthroscopy) were screened. Participants were enrolled from May 25, 2010, to July 25, 2014, and followed up for 2 years postoperatively. Intention-to-treat analysis was used in evaluation of the findings.Gabapentin, 1200 mg, preoperatively and 600 mg, 3 times a day postoperatively or active placebo (lorazepam, 0.5 mg) preoperatively followed by inactive placebo postoperatively for 72 hours.Primary outcome was time to pain resolution (5 consecutive reports of 0 of 10 possible levels of average pain at the surgical site on the numeric rating scale of pain). Secondary outcomes were time to opioid cessation (5 consecutive reports of no opioid use) and the proportion of participants with continued pain or opioid use at 6 months and 1 year.Of 1805 patients screened for enrollment, 1383 were excluded, including 926 who did not meet inclusion criteria and 273 who declined to participate. Overall, 8% of patients randomized were lost to follow-up. A total of 202 patients were randomized to active placebo and 208 patients were randomized to gabapentin in the intention-to-treat analysis (mean [SD] age, 56.7 [11.7] years; 256 (62.4%) women and 154 (37.6%) men). Baseline characteristics of the groups were similar. Perioperative gabapentin did not affect time to pain cessation (hazard ratio [HR], 1.04; 95% CI, 0.82-1.33; P = .73) in the intention-to-treat analysis. However, participants receiving gabapentin had a 24% increase in the rate of opioid cessation after surgery (HR, 1.24; 95% CI, 1.00-1.54; P = .05). No significant differences were noted in the number of adverse events as well as the rate of medication discontinuation due to sedation or dizziness (placebo, 42 of 202 [20.8%]; gabapentin, 52 of 208 [25.0%]).Perioperative administration of gabapentin had no effect on postoperative pain resolution, but it had a modest effect on promoting opioid cessation after surgery. The routine use of perioperative gabapentin may be warranted to promote opioid cessation and prevent chronic opioid use. Optimal dosing and timing of perioperative gabapentin in the context of specific operations to decrease opioid use should be addressed in further research.clinicaltrials.gov Identifier: NCT01067144.

Abstract

Chronic inflammation, a decline in immune responsiveness, and reduced cardiovascular function are all associated with aging, but the relationships among these phenomena remain unclear. Here, we longitudinally profiled a total of 84 signaling conditions in 91 young and older adults and observed an age-related reduction in cytokine responsiveness within four immune cell lineages, most prominently T cells. The phenotype can be partially explained by elevated baseline levels of phosphorylated STAT (pSTAT) proteins and a different response capacity of naive versus memory T cell subsets to interleukin 6 (IL-6), interferon α (IFN-α), and, to a lesser extent, IL-21 and IFN-γ. Baseline pSTAT levels tracked with circulating levels of C-reactive protein (CRP), and we derived a cytokine response score that negatively correlates with measures of cardiovascular disease, specifically diastolic dysfunction and atherosclerotic burden, outperforming CRP. Thus, we identified an immunological link between inflammation, decreased cell responsiveness in the JAK-STAT pathway, and cardiovascular aging. Targeting chronic inflammation may ameliorate this deficiency in cellular responsiveness and improve cardiovascular function.

Abstract

National Pain Strategy population research objectives include: estimating chronic pain prevalence, studying pain treatment with electronic health care data, and developing metrics to assess progress in reducing chronic pain impact. In this article, the National Pain Strategy Population Research Workgroup reviews concepts relevant to achieving these aims. High-impact chronic pain was defined as persistent pain with substantial restriction of life activities lasting 6 months or more. In pilot work, we tested a brief assessment of high-impact chronic pain, and used electronic health records data to describe pain-related health care. A mail survey of adult health plan enrollees (N = 770) reported that 14% had high-impact chronic pain. Relative to persons with lower-impact chronic pain, those with high-impact chronic pain were more often frequent users of health care for pain, reported lower quality of life, greater pain-related interference with activities, and more often reported pain at multiple anatomic locations. Analyses of health care data (N = 289,464) reported that pain patients had higher health care costs compared with others and that pain services were typically delivered in primary care. These results support the feasibility of developing data on chronic pain through national health interview surveys and large electronic health care databases.Pilot analyses supported the feasibility of brief chronic pain assessments suitable for national health surveys and use of electronic health care databases to develop data regarding trends in the delivery of pain treatments, costs, and effectiveness. These methods are relevant to achieving the aims of the US National Pain Strategy.

Abstract

Maladaptive responses to pain-related distress, such as pain catastrophizing, amplify the impairments associated with chronic pain. Many of these aspects of chronic pain are similar to affective distress in clinical anxiety disorders. In light of the role of the amygdala in pain and affective distress, disruption of amygdalar functional connectivity in anxiety states, and its implication in the response to noxious stimuli, we investigated amygdala functional connectivity in 17 patients with chronic low back pain and 17 healthy comparison subjects, with respect to normal targets of amygdala subregions (basolateral vs centromedial nuclei), and connectivity to large-scale cognitive-emotional networks, including the default mode network, central executive network, and salience network. We found that patients with chronic pain had exaggerated and abnormal amygdala connectivity with central executive network, which was most exaggerated in patients with the greatest pain catastrophizing. We also found that the normally basolateral-predominant amygdala connectivity to the default mode network was blunted in patients with chronic pain. Our results therefore highlight the importance of the amygdala and its network-level interaction with large-scale cognitive/affective cortical networks in chronic pain, and help link the neurobiological mechanisms of cognitive theories for pain with other clinical states of affective distress.

Abstract

Chronic opioid use imposes a substantial burden in terms of morbidity and economic costs. Whether opioid-naive patients undergoing surgery are at increased risk for chronic opioid use is unknown, as are the potential risk factors for chronic opioid use following surgery.To characterize the risk of chronic opioid use among opioid-naive patients following 1 of 11 surgical procedures compared with nonsurgical patients.Retrospective analysis of administrative health claims to determine the association between chronic opioid use and surgery among privately insured patients between January 1, 2001, and December 31, 2013. The data concluded 11 surgical procedures (total knee arthroplasty [TKA], total hip arthroplasty, laparoscopic cholecystectomy, open cholecystectomy, laparoscopic appendectomy, open appendectomy, cesarean delivery, functional endoscopic sinus surgery [FESS], cataract surgery, transurethral prostate resection [TURP], and simple mastectomy). Multivariable logistic regression analysis was performed to control for possible confounders, including sex, age, preoperative history of depression, psychosis, drug or alcohol abuse, and preoperatice use of benzodiazepines, antipsychotics, and antidepressants.One of the 11 study surgical procedures.Chronic opioid use, defined as having filled 10 or more prescriptions or more than 120 days' supply of an opioid in the first year after surgery, excluding the first 90 postoperative days. For nonsurgical patients, chronic opioid use was defined as having filled 10 or more prescriptions or more than 120 days' supply following a randomly assigned "surgery date."The study included 641 941 opioid-naive surgical patients (169 666 men; mean [SD] age, 44.0 [12.8] years), and 18 011 137 opioid-naive nonsurgical patients (8 849 107 men; mean [SD] age, 42.4 [12.6] years). Among the surgical patients, the incidence of chronic opioid in the first preoperative year ranged from 0.119% for Cesarean delivery (95% CI, 0.104%-0.134%) to 1.41% for TKA (95% CI, 1.29%-1.53%) The baseline incidence of chronic opioid use among the nonsurgical patients was 0.136% (95% CI, 0.134%-0.137%). Except for cataract surgery, laparoscopic appendectomy, FESS, and TURP, all of the surgical procedures were associated with an increased risk of chronic opioid use, with odds ratios ranging from 1.28 (95% CI, 1.12-1.46) for cesarean delivery to 5.10 (95% CI, 4.67-5.58) for TKA. Male sex, age older than 50 years, and preoperative history of drug abuse, alcohol abuse, depression, benzodiazepine use, or antidepressant use were associated with chronic opioid use among surgical patients.In opioid-naive patients, many surgical procedures are associated with an increased risk of chronic opioid use in the postoperative period. A certain subset of patients (eg, men, elderly patients) may be particularly vulnerable.

Abstract

The pediatric adaptation of the Collaborative Health Outcomes Information Registry (Peds-CHOIR) is a free, open-source, flexible learning health care system (LHS) that meets the call by the Institute of Medicine for the development of national registries to guide research and precision pain medicine. This report is a technical account of the first application of Peds-CHOIR with 3 aims: (1) to describe the design and implementation process of the LHS; (2) to highlight how the clinical system concurrently cultivates a research platform rich in breadth (eg, clinic characteristics) and depth (eg, unique patient- and caregiver-reporting patterns); and (3) to demonstrate the utility of capturing patient-caregiver dyad data in real time, with dynamic outcomes tracking that informs clinical decisions and delivery of treatments. Technical, financial, and systems-based considerations of Peds-CHOIR are discussed. Cross-sectional retrospective data from patients with chronic pain (N = 352; range, 8-17 years; mean, 13.9 years) and their caregivers are reported, including National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) domains (mobility, pain interference, fatigue, peer relations, anxiety, and depression) and the Pain Catastrophizing Scale. Consistent with the literature, analyses of initial visits revealed impairments across physical, psychological, and social domains. Patients and caregivers evidenced agreement in observable variables (mobility); however, caregivers consistently endorsed greater impairment regarding internal experiences (pain interference, fatigue, peer relations, anxiety, and depression) than patients' self-report. A platform like Peds-CHOIR highlights predictors of chronic pain outcomes on a group level and facilitates individually tailored treatment(s). Challenges of implementation and future directions are discussed.

Abstract

Limited research suggests that there may be Warm complex regional pain syndrome (CRPS) and Cold CRPS subtypes, with inflammatory mechanisms contributing most strongly to the former. This study for the first time used an unbiased statistical pattern recognition technique to evaluate whether distinct Warm vs Cold CRPS subtypes can be discerned in the clinical population. An international, multisite study was conducted using standardized procedures to evaluate signs and symptoms in 152 patients with clinical CRPS at baseline, with 3-month follow-up evaluations in 112 of these patients. Two-step cluster analysis using automated cluster selection identified a 2-cluster solution as optimal. Results revealed a Warm CRPS patient cluster characterized by a warm, red, edematous, and sweaty extremity and a Cold CRPS patient cluster characterized by a cold, blue, and less edematous extremity. Median pain duration was significantly (P < 0.001) shorter in the Warm CRPS (4.7 months) than in the Cold CRPS subtype (20 months), with pain intensity comparable. A derived total inflammatory score was significantly (P < 0.001) elevated in the Warm CRPS group (compared with Cold CRPS) at baseline but diminished significantly (P < 0.001) over the follow-up period, whereas this score did not diminish in the Cold CRPS group (time × subtype interaction: P < 0.001). Results support the existence of a Warm CRPS subtype common in patients with acute (<6 months) CRPS and a relatively distinct Cold CRPS subtype most common in chronic CRPS. The pattern of clinical features suggests that inflammatory mechanisms contribute most prominently to the Warm CRPS subtype but that these mechanisms diminish substantially during the first year postinjury.

Abstract

Perceptions of pain as unfair are a significant risk factor for poorer physical and psychological outcomes in acute injury and chronic pain. Chief among the negative emotions associated with perceived injustice is anger, arising through frustration of personal goals and unmet expectations regarding others' behavior. However, despite a theoretical connection with anger, the social mediators of perceived injustice have not been demonstrated in chronic pain.The current study examined two socially based variables and a broader measure of pain interference as mediators of the relationships between perceived injustice and both anger and pain intensity in a sample of 302 patients in a tertiary care pain clinic setting.Data from the Collaborative Health Outcomes Information Registry (CHOIR) were analyzed using cross-sectional path modeling analyses to examine social isolation, satisfaction with social roles and activities, and pain-related interference as potential mediators of the relationships between perceived injustice and both anger and pain intensity.When modeled simultaneously, ratings of social isolation mediated the relationship between perceived injustice and anger, while pain-related interference and social satisfaction did not. Neither social variable was found to mediate the relationship between perceived injustice and pain intensity, however.The current findings highlight the strongly interpersonal nature of perceived injustice and anger in chronic pain, though these effects do not appear to extend to the intensity of pain itself. Nevertheless, the results highlight the need for interventions that ameliorate both maladaptive cognitive appraisal of pain and pain-related disruptions in social relationships.

Abstract

Sensory hypersensitivity is one manifestation of the central sensitization that may underlie conditions such as fibromyalgia and chronic fatigue syndrome. We conducted five studies designed to develop and validate the Sensory Hypersensitive Scale (SHS); a 25-item self-report measure of sensory hypersensitivity. The SHS assesses both general sensitivity and modality-specific sensitivity (e.g. touch, taste, and hearing). 1202 participants (157 individuals with chronic pain) completed the SHS, which demonstrated an adequate overall internal reliability (Cronbach's alpha) of 0.81, suggesting the tool can be used as a cross-modality assessment of sensitivity. SHS scores demonstrated only modest correlations (Pearson's r) with depressive symptoms (0.19) and anxiety (0.28), suggesting a low level of overlap with psychiatric complaints. Overall SHS scores showed significant but relatively modest correlations (Pearson's r) with three measures of sensory testing: cold pain tolerance (-0.34); heat pain tolerance (-0.285); heat pain threshold (-0.271). Women reported significantly higher scores on the SHS than did men, although gender-based differences were small. In a chronic pain sample, individuals with fibromyalgia syndrome demonstrated significantly higher SHS scores than did individuals with osteoarthritis or back pain. The SHS appears suitable as a screening measure for sensory hypersensitivity, though additional research is warranted to determine its suitability as a proxy for central sensitization.

Abstract

The challenges and understanding of acute and chronic pain have been illuminated through the advancement of central neuroimaging. Through neuroimaging research, new technology and findings have allowed us to identify and understand the neural mechanisms contributing to chronic pain. Several regions of the brain are known to be of particular importance for the maintenance and amplification of chronic pain, and this knowledge provides novel targets for future research and treatment. This article reviews neuroimaging for the study of chronic pain, and in particular, the rapidly advancing and popular research tools of structural and functional MRI.

Abstract

We describe here Survalytics, a software module designed to address two broad areas of need. The first area is in the domain of surveys and app analytics: developers of mobile apps in both academic and commercial environments require information about their users, as well as how the apps are being used, to understand who their users are and how to optimally approach app development. The second area of need is in the field of ecological momentary assessment, also referred to as experience sampling: researchers in a wide variety of fields, spanning from the social sciences to psychology to clinical medicine, would like to be able to capture daily or even more frequent data from research subjects while in their natural environment.Survalytics is an open-source solution for the collection of survey responses as well as arbitrary analytic metadata from users of Android operating system apps.Surveys may be administered in any combination of one-time questions and ongoing questions. The module may be deployed as a stand-alone app for experience sampling purposes or as an add-on to existing apps. The module takes advantage of free-tier NoSQL cloud database management offered by the Amazon Web Services DynamoDB platform to package a secure, flexible, extensible data collection module. DynamoDB is capable of Health Insurance Portability and Accountability Act compliant storage of personal health information.The provided example app may be used without modification for a basic experience sampling project, and we provide example questions for daily collection of blood glucose data from study subjects.The module will help researchers in a wide variety of fields rapidly develop tailor-made Android apps for a variety of data collection purposes.

Abstract

Neural models of major depressive disorder (MDD) posit that over-response of components of the brain's salience network (SN) to negative stimuli plays a crucial role in the pathophysiology of MDD. In the present proof-of-concept study, we tested this formulation directly by examining the affective consequences of training depressed persons to down-regulate response of SN nodes to negative material. Ten participants in the real neurofeedback group saw, and attempted to learn to down-regulate, activity from an empirically identified node of the SN. Ten other participants engaged in an equivalent procedure with the exception that they saw SN-node neurofeedback indices from participants in the real neurofeedback group. Before and after scanning, all participants completed tasks assessing emotional responses to negative scenes and to negative and positive self-descriptive adjectives. Compared to participants in the sham-neurofeedback group, from pre- to post-training, participants in the real-neurofeedback group showed a greater decrease in SN-node response to negative stimuli, a greater decrease in self-reported emotional response to negative scenes, and a greater decrease in self-reported emotional response to negative self-descriptive adjectives. Our findings provide support for a neural formulation in which the SN plays a primary role in contributing to negative cognitive biases in MDD.

Abstract

The Institute of Medicine and the draft National Pain Strategy recently called for better training for health care clinicians. This was the first high-level needs assessment for pain psychology services and resources in the United States.Prospective, observational, cross-sectional.Brief surveys were administered online to six stakeholder groups (psychologists/therapists, individuals with chronic pain, pain physicians, primary care physicians/physician assistants, nurse practitioners, and the directors of graduate and postgraduate psychology training programs).1,991 responses were received. Results revealed low confidence and low perceived competency to address physical pain among psychologists/therapists, and high levels of interest and need for pain education. We found broad support for pain psychology across stakeholder groups, and global support for a national initiative to increase pain training and competency in U.S. therapists. Among directors of graduate and postgraduate psychology training programs, we found unanimous interest for a no-cost pain psychology curriculum that could be integrated into existing programs. Primary barriers to pain psychology include lack of a system to identify qualified therapists, paucity of therapists with pain training, limited awareness of the psychological treatment modality, and poor insurance coverage.This report calls for transformation within psychology predoctoral and postdoctoral education and training and psychology continuing education to include and emphasize pain and pain management. A system for certification is needed to facilitate quality control and appropriate reimbursement. There is a need for systems to facilitate identification and access to practicing psychologists and therapists skilled in the treatment of pain.

Abstract

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network is an ongoing multi-center collaborative research group established to conduct integrated studies in participants with urologic chronic pelvic pain syndrome (UCPPS). The goal of these investigations is to provide new insights into the etiology, natural history, clinical, demographic and behavioral characteristics, search for new and evaluate candidate biomarkers, systematically test for contributions of infectious agents to symptoms, and conduct animal studies to understand underlying mechanisms for UCPPS. Study participants were enrolled in a one-year observational study and evaluated through a multisite, collaborative neuroimaging study to evaluate the association between UCPPS and brain structure and function. 3D T1-weighted structural images, resting-state fMRI, and high angular resolution diffusion MRI were acquired in five participating MAPP Network sites using 8 separate MRI hardware and software configurations. We describe the neuroimaging methods and procedures used to scan participants, the challenges encountered in obtaining data from multiple sites with different equipment/software, and our efforts to minimize site-to-site variation.

Abstract

In this case report, the authors describe the implementation of a system for collecting patient-reported outcomes and integrating results in an electronic health record. The objective was to identify lessons learned in overcoming barriers to collecting and integrating patient-reported outcomes in an electronic health record. The authors analyzed qualitative data in 42 documents collected from system development meetings, written feedback from users, and clinical observations with practice staff, providers, and patients. Guided by the Unified Theory on the Adoption and Use of Information Technology, 5 emergent themes were identified. Two barriers emerged: (i) uncertain clinical benefit and (ii) time, work flow, and effort constraints. Three facilitators emerged: (iii) process automation, (iv) usable system interfaces, and (v) collecting patient-reported outcomes for the right patient at the right time. For electronic health record-integrated patient-reported outcomes to succeed as useful clinical tools, system designers must ensure the clinical relevance of the information being collected while minimizing provider, staff, and patient burden.

Abstract

Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

Abstract

Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

Abstract

Individuals with chronic pain show a greater vulnerability to depression or anger than those without chronic pain, and also show greater interpersonal difficulties and physical disability. The current study examined data from 675 individuals with chronic pain during their initial visits to a tertiary care pain clinic using assessments from Stanford University's Collaborative Health Outcomes Information Registry (CHOIR). Using a path modeling analysis, the mediating roles of PROMIS Physical Function and PROMIS Satisfaction with Social Roles and Activities were tested between pain intensity and PROMIS Depression and Anger. Pain intensity significantly predicted both depression and anger, and both physical function and satisfaction with social roles mediated these relationships when modeled in separate 1-mediator models. Notably, however, when modeled together, ratings of satisfaction with social roles mediated the relationship between physical function and both anger and depression. Our results suggest that the process by which chronic pain disrupts emotional well-being involves both physical function and disrupted social functioning. However, the more salient factor in determining pain-related emotional distress appears to be disruption of social relationships, rather than global physical impairment. These results highlight the particular importance of social factors to pain-related distress, and highlight social functioning as an important target for clinical intervention in chronic pain.

Abstract

Consensus indicates that a comprehensive,multimodal, holistic approach is foundational to the practice of acute pain medicine (APM),but lack of uniform, evidence-based clinical pathways leads to undesirable variability throughout U. S. healthcare systems. Acute pain studies are inconsistently synthesized to guide educational programs. Advanced practice techniques involving regional anesthesia assume the presence of a physician-led, multidisciplinary acute pain service,which is often unavailable or inconsistently applied.This heterogeneity of educational and organizational standards may result in unnecessary patient pain and escalation of healthcare costs.A multidisciplinary panel was nominated through the APM Shared Interest Group of the American Academy of Pain Medicine. The panel met in Chicago, IL, in July 2014, to identify gaps and set priorities in APM research and education.The panel identified three areas of critical need: 1) an open-source acute pain data registry and clinical support tool to inform clinical decision making and resource allocation and to enhance research efforts; 2) a strong professional APM identity as an accredited subspecialty; and 3) educational goals targeted toward third-party payers,hospital administrators, and other key stake holders to convey the importance of APM.This report is the first step in a 3-year initiative aimed at creating conditions and incentives for the optimal provision of APM services to facilitate and enhance the quality of patient recovery after surgery, illness, or trauma. The ultimate goal is to reduce the conversion of acute pain to the debilitating disease of chronic pain.

Abstract

Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific, and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. The NIH Pain Consortium therefore charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimal data set to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect the RTF recommendations will become a dynamic document, and undergo continual improvement.A Task Force was convened by the NIH Pain Consortium, with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimal dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

Abstract

Several chronic pain conditions may be distinguished by condition specific brain anatomical and functional abnormalities on imaging, which are suggestive of underlying disease processes. We present what is to our knowledge the first characterization of interstitial cystitis/bladder pain syndrome associated white matter (axonal) abnormalities based on multicenter neuroimaging from the MAPP Research Network.We assessed 34 women with interstitial cystitis/bladder pain syndrome and 32 healthy controls using questionnaires on pain, mood and daily function. White matter microstructure was evaluated by diffusion tensor imaging to model directional water flow along axons or fractional anisotropy. Regions correlating with clinical parameters were further examined for gender and syndrome dependence.Women with interstitial cystitis/bladder pain syndrome showed numerous white matter abnormalities that correlated with pain severity, urinary symptoms and impaired quality of life. Interstitial cystitis/bladder pain syndrome was characterized by decreased fractional anisotropy in aspects of the right anterior thalamic radiation, the left forceps major and the right longitudinal fasciculus. Increased fractional anisotropy was detected in the right superior and bilateral inferior longitudinal fasciculi.To our knowledge we report the first characterization of brain white matter abnormalities in women with interstitial cystitis/bladder pain syndrome. Regional decreases and increases in white matter integrity across multiple axonal tracts were associated with symptom severity. Given that white matter abnormalities closely correlated with hallmark symptoms of interstitial cystitis/bladder pain syndrome, including bladder pain and urinary symptoms, brain anatomical alterations suggest that there are neuropathological contributions to chronic urological pelvic pain.

Abstract

A bidirectional relationship between working memory (WM) and acute pain has long been assumed, but equivocal evidence exists regarding this relationship. This study characterized the relationship between WM and acute pain processing in healthy individuals using an adapted Sternberg WM task.Participants completed a Sternberg task while receiving noxious thermal stimulation. Participants received a pseudorandom presentation of four different temperatures (baseline temperatures and individually determined low-, medium-, and high-temperature stimuli) and four levels of Sternberg task difficulty (0-, 3-, 6-, and 9-letter strings).Twenty-eight healthy participants were recruited from Stanford University and the surrounding community to complete this study.A nonlinear interaction between intensity of thermal stimulation and difficulty of the Sternberg task was noted. Increased cognitive load from the Sternberg task resulted in increased perception of pain in low-intensity thermal stimulation but suppressed pain perception in high-intensity thermal stimulation. Thermal stimulation had no significant effect on participants' response time or accuracy on the Sternberg task regardless of intensity level.Pain perception appears to decrease as a function of WM load only for sufficiently noxious stimuli. However, increasing noxious stimuli did not affect cognitive performance. These complex relationships may reflect a shared cognitive space that can become "overloaded" with input of multiple stimuli of sufficient intensity.

Abstract

Fatigue is a multidimensional construct that has significant implications for physical function in chronic non-cancer pain populations but remains relatively understudied. The current study characterized the independent contributions of self-reported ratings of pain intensity, sleep disturbance, depression, and fatigue to ratings of physical function and pain-related interference in a diverse sample of treatment-seeking individuals with chronic pain. Methods: These relationships were examined as a path modeling analysis of self-report scores obtained from 2,487 individuals with chronic pain from a tertiary care outpatient pain clinic.Our analyses revealed unique relationships of pain intensity, sleep disturbance, and depression with self-reported fatigue. Further, fatigue scores accounted for significant proportions of the relationships of both pain intensity and depression with physical function and pain-related interference, and accounted for the entirety of the unique statistical relationship between sleep disturbance and both physical function and pain-related interference.Fatigue is a complex construct with relationships to both physical and psychological factors that has significant implications for physical functioning in chronic non-cancer pain. The current results identify potential targets for future treatment of fatigue in chronic pain, and may provide directions for future clinical and theoretical research in the area of chronic non-cancer pain.Fatigue is an important physical and psychological variable that factors prominently in the deleterious consequences of pain intensity, sleep disturbance, and depression for physical function in chronic non-cancer pain.

Abstract

Fatigue is a multidimensional construct that has significant implications for physical function in chronic non-cancer pain populations but remains relatively understudied. The current study characterized the independent contributions of self-reported ratings of pain intensity, sleep disturbance, depression, and fatigue to ratings of physical function and pain-related interference in a diverse sample of treatment-seeking individuals with chronic pain. Methods: These relationships were examined as a path modeling analysis of self-report scores obtained from 2,487 individuals with chronic pain from a tertiary care outpatient pain clinic.Our analyses revealed unique relationships of pain intensity, sleep disturbance, and depression with self-reported fatigue. Further, fatigue scores accounted for significant proportions of the relationships of both pain intensity and depression with physical function and pain-related interference, and accounted for the entirety of the unique statistical relationship between sleep disturbance and both physical function and pain-related interference.Fatigue is a complex construct with relationships to both physical and psychological factors that has significant implications for physical functioning in chronic non-cancer pain. The current results identify potential targets for future treatment of fatigue in chronic pain, and may provide directions for future clinical and theoretical research in the area of chronic non-cancer pain.Fatigue is an important physical and psychological variable that factors prominently in the deleterious consequences of pain intensity, sleep disturbance, and depression for physical function in chronic non-cancer pain.

Abstract

Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

Abstract

Interstitial cystitis is a highly prevalent pain condition estimated to affect 3% to 6% of women in the United States. Emerging data suggest there are central neurobiological components to the etiology of this disease. We report the first brain structural imaging findings from the MAPP network with data on more than 300 participants.We used voxel based morphometry to determine whether human patients with chronic interstitial cystitis display changes in brain morphology compared to healthy controls. A total of 33 female patients with interstitial cystitis without comorbidities and 33 age and gender matched controls taken from the larger sample underwent structural magnetic resonance imaging at 5 MAPP sites across the United States.Compared to controls, females with interstitial cystitis displayed significant increased gray matter volume in several regions of the brain including the right primary somatosensory cortex, the superior parietal lobule bilaterally and the right supplementary motor area. Gray matter volume in the right primary somatosensory cortex was associated with greater pain, mood (anxiety) and urological symptoms. We explored these correlations in a linear regression model, and found independent effects of these 3 measures on primary somatosensory cortex gray matter volume, namely clinical pain (McGill pain sensory total), a measure of urgency and anxiety (HADS).These data support the notion that changes in somatosensory gray matter may have an important role in pain sensitivity as well as affective and sensory aspects of interstitial cystitis. Further studies are needed to confirm the generalizability of these findings to other pain conditions.

Abstract

Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing.

Neuroimaging chronic pain: what have we learned and where are we going?Future neurologyMartucci, K. T., Ng, P., Mackey, S.2014; 9 (6): 615-626

Abstract

Advances in neuroimaging have helped illuminate our understanding of how the brain works in the presence of chronic pain, which often persists with unknown etiology or after the painful stimulus has been removed and any wounds have healed. Neuroimaging has enabled us to make great progress in identifying many of the neural mechanisms that contribute to chronic pain, and to pinpoint the specific regions of the brain that are activated in the presence of chronic pain. It has provided us with a new perception of the nature of chronic pain in general, leading researchers to move toward a whole-brain approach to the study and treatment of chronic pain, and to develop novel technologies and analysis techniques, with real potential for developing new diagnostics and more effective therapies. We review the use of neuroimaging in the study of chronic pain, with particular emphasis on magnetic resonance imaging.

Abstract

Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

Abstract

Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed nonspecific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. The purpose of this article is to disseminate the report of the National Institutes of Health (NIH) task force on research standards for cLBP.The NIH Pain Consortium charged a research task force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel developed a 3-stage process, each with a 2-day meeting.The panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimal data set to describe research subjects (drawing heavily on the Patient Reported Outcomes Measurement Information System methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved these recommendations, which investigators should incorporate into NIH grant proposals.The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of cLBP. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. We expect the RTF recommendations will become a dynamic document and undergo continual improvement.

Abstract

The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications.The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar.Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated.Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation.

Abstract

Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus.The NIH Pain Consortium therefore charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel developed a 3-stage process, each with a 2-day meeting.The panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals.The RTF believes these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement.

Abstract

Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

Abstract

The "Multidisciplinary Approach to the Study of Chronic Pelvic Pain" (MAPP) Research Network was established by the NIDDK to better understand the pathophysiology of urologic chronic pelvic pain syndromes (UCPPS), to inform future clinical trials and improve clinical care. The evolution, organization, and scientific scope of the MAPP Research Network, and the unique approach of the network's central study and common data elements are described.The primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multi-site, longitudinal observational study, including bi-weekly internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms and psychosocial factors to evaluate men and women with UCPPS. Healthy controls, matched on sex and age, as well as "positive" controls meeting the non-urologic associated syndromes (NUAS) criteria for one or more of the target conditions of Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) or Irritable Bowel Syndrome (IBS), were also evaluated. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Recruitment into the central study occurred at six Discovery Sites in the United States, resulting in a total of 1,039 enrolled participants, exceeding the original targets. The biospecimen collection rate at baseline visits reached nearly 100%, and 279 participants underwent common neuroimaging through a standardized protocol. An extended follow-up study for 161 of the UCPPS participants is ongoing.The MAPP Research Network represents a novel, comprehensive approach to the study of UCPPS, as well as other concomitant NUAS. Findings are expected to provide significant advances in understanding UCPPS pathophysiology that will ultimately inform future clinical trials and lead to improvements in patient care. Furthermore, the structure and methodologies developed by the MAPP Network provide the foundation upon which future studies of other urologic or non-urologic disorders can be based.ClinicalTrials.gov identifier: NCT01098279 "Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)". http://clinicaltrials.gov/show/NCT01098279.

Abstract

Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific, and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus.Expert panel and preliminary evaluation of key recommendations.The NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel developed a 3-stage process, each with a 2-day meeting.The panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimal data set to describe research subjects (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals.The RTF believes these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. We expect the RTF recommendations will become a dynamic document, and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

Abstract

Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed nonspecific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a research task force to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum data set to describe research participants (drawing heavily on the Patient Reported Outcomes Measurement Information System methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The research task force believes that these recommendations will advance the field, help resolve controversies, and facilitate future research addressing the genomic, neurological, and other mechanistic substrates of cLBP. We expect that the research task force recommendations will become a dynamic document and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for cLBP. The results included recommendations for definitions, a minimum data set, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

Abstract

We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

Abstract

Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

Abstract

We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

Abstract

Individuals involved in the early stages of a passionate romantic relationship can be consumed by the experience and report emotional dependence and constant focus on their romantic partner. A few studies have shown that viewing pictures of a romantic partner can significantly reduce experimental pain. The strength of the effect, however, varies substantially between individuals. To study why some individuals experience significant pain reduction when looking at a picture of their partner, we examined partner preoccupation. We hypothesized that a greater degree of preoccupation in the early stages of a romantic relationship would be associated with greater analgesia during a pain induction task.Participants were shown pictures of their romantic partner or an equally attractive and familiar acquaintance while exposed to low, moderate, or high levels of thermal pain. Participants were also asked to rate how much time they spent thinking about their romantic partner during an average day. Degree of preoccupation was defined as the percentage of time participants spent thinking about their partner on an average day.In two separate experiments, viewing pictures of a romantic partner produced an analgesic effect. The degree of pain relief was positively correlated with partner preoccupation. The results suggest that preoccupation with a romantic partner during early stage romantic love is a predictor of pain relief when viewing pictures of the beloved.

Abstract

Chronic low back pain (cLBP) has a tremendous personal and socioeconomic impact, yet the underlying pathology remains a mystery in the majority of cases. An objective measure of this condition, that augments self-report of pain, could have profound implications for diagnostic characterization and therapeutic development. Contemporary research indicates that cLBP is associated with abnormal brain structure and function. Multivariate analyses have shown potential to detect a number of neurological diseases based on structural neuroimaging. Therefore, we aimed to empirically evaluate such an approach in the detection of cLBP, with a goal to also explore the relevant neuroanatomy. We extracted brain gray matter (GM) density from magnetic resonance imaging scans of 47 patients with cLBP and 47 healthy controls. cLBP was classified with an accuracy of 76% by support vector machine analysis. Primary drivers of the classification included areas of the somatosensory, motor, and prefrontal cortices--all areas implicated in the pain experience. Differences in areas of the temporal lobe, including bordering the amygdala, medial orbital gyrus, cerebellum, and visual cortex, were also useful for the classification. Our findings suggest that cLBP is characterized by a pattern of GM changes that can have discriminative power and reflect relevant pathological brain morphology.

Abstract

Complex regional pain syndrome (CRPS) is a chronic condition that involves significant hyperalgesia of the affected limb, typically accompanied by localized autonomic abnormalities and frequently by motor dysfunction. Although central brain systems are thought to play a role in the development and maintenance of CRPS, these systems have not been well characterized. In this study, we used structural magnetic resonance imaging to characterize differences in gray matter volume between patients with right upper extremity CRPS and matched controls. Analyses were carried out using a whole brain voxel-based morphometry approach. The CRPS group showed decreased gray matter volume in several pain-affect regions, including the dorsal insula, left orbitofrontal cortex, and several aspects of the cingulate cortex. Greater gray matter volume in CRPS patients was seen in the bilateral dorsal putamen and right hypothalamus. Correlation analyses with self-reported pain were then performed on the CRPS group. Pain duration was associated with decreased gray matter in the left dorsolateral prefrontal cortex. Pain intensity was positively correlated with volume in the left posterior hippocampus and left amygdala, and negatively correlated with the bilateral dorsolateral prefrontal cortex. Our findings demonstrate that CRPS is associated with abnormal brain system morphology, particularly pain-related sensory, affect, motor, and autonomic systems.This paper presents structural changes in the brains of patients with CRPS, helping us differentiate CRPS from other chronic pain syndromes and furthering our understanding of this challenging disease.

Abstract

Conditioned pain modulation (CPM) is an experimental approach for probing endogenous analgesia by which one painful stimulus (the conditioning stimulus) may inhibit the perceived pain of a subsequent stimulus (the test stimulus). Animal studies suggest that CPM is mediated by a spino-bulbo-spinal loop using objective measures such as neuronal firing. In humans, pain ratings are often used as the end point. Because pain self-reports are subject to cognitive influences, we tested whether cognitive factors would impact on CPM results in healthy humans.We conducted a within-subject, crossover study of healthy adults to determine the extent to which CPM is affected by 1) threatening and reassuring evaluation and 2) imagery alone of a cold conditioning stimulus. We used a heat stimulus individualized to 5/10 on a visual analog scale as the testing stimulus and computed the magnitude of CPM by subtracting the postconditioning rating from the baseline pain rating of the heat stimulus.We found that although evaluation can increase the pain rating of the conditioning stimulus, it did not significantly alter the magnitude of CPM. We also found that imagery of cold pain alone did not result in statistically significant CPM effect.Our results suggest that CPM is primarily dependent on sensory input, and that the cortical processes of evaluation and imagery have little impact on CPM. These findings lend support for CPM as a useful tool for probing endogenous analgesia through subcortical mechanisms.

Abstract

The emergence of anger as an important predictor of chronic pain outcomes suggests that treatments that target anger may be particularly useful within the context of chronic pain. Eastern traditions prescribe compassion cultivation to treat persistent anger. Compassion cultivation has been shown to influence emotional processing and reduce negativity bias in the contexts of emotional and physical discomfort, thus suggesting it may be beneficial as a dual treatment for pain and anger. Our objective was to conduct a pilot study of a 9-week group compassion cultivation intervention in chronic pain to examine its effect on pain severity, anger, pain acceptance and pain-related interference. We also aimed to describe observer ratings provided by patients' significant others and secondary effects of the intervention.Pilot clinical trial with repeated measures design that included a within-subjects wait-list control period. Twelve chronic pain patients completed the intervention (F= 10). Data were collected from patients at enrollment, treatment baseline and post-treatment; participant significant others contributed data at the enrollment and post-treatment time points.In this predominantly female sample, patients had significantly reduced pain severity and anger and increased pain acceptance at post-treatment compared to treatment baseline. Significant other qualitative data corroborated patient reports for reductions in pain severity and anger.Compassion meditation may be a useful adjunctive treatment for reducing pain severity and anger, and for increasing chronic pain acceptance. Patient reported reductions in anger were corroborated by their significant others. The significant other corroborations offer a novel contribution to the literature and highlight the observable emotional and behavioral changes in the patient participants that occurred following the compassion intervention. Future studies may further examine how anger reductions impact relationships with self and others within the context of chronic pain.

Abstract

Pain catastrophizing (PC) - a pattern of negative cognitive-emotional responses to real or anticipated pain - maintains chronic pain and undermines medical treatments. Standard PC treatment involves multiple sessions of cognitive behavioral therapy. To provide efficient treatment, we developed a single-session, 2-hour class that solely treats PC entitled "From Catastrophizing to Recovery" [FCR].To determine 1) feasibility of FCR; 2) participant ratings for acceptability, understandability, satisfaction, and likelihood to use the information learned; and 3) preliminary efficacy of FCR for reducing PC.Uncontrolled prospective pilot trial with a retrospective chart and database review component. Seventy-six patients receiving care at an outpatient pain clinic (the Stanford Pain Management Center) attended the class as free treatment and 70 attendees completed and returned an anonymous survey immediately post-class. The Pain Catastrophizing Scale (PCS) was administered at class check-in (baseline) and at 2, and 4 weeks post-treatment. Within subjects repeated measures analysis of variance (ANOVA) with Student's t-test contrasts were used to compare scores across time points.All attendees who completed a baseline PCS were included as study participants (N=57; F=82%; mean age =50.2 years); PCS was completed by 46 participants at week 2 and 35 participants at week 4. Participants had significantly reduced PC at both time points (P<0001) and large effect sizes were found (Cohen's d=0.85 and d=1.15).Preliminary data suggest that FCR is an acceptable and effective treatment for PC. Larger, controlled studies of longer duration are needed to determine durability of response, factors contributing to response, and the impact on pain, function and quality of life.

Abstract

Though fibromyalgia is not traditionally considered an inflammatory disorder, evidence for elevated inflammatory processes has been noted in this disorder in multiple studies. Support for inflammatory markers in fibromyalgia has been somewhat equivocal to date, potentially due to inattention to salient patient characteristics that may affect inflammation, such as psychiatric distress and aging milestones like menopause. The current study examined the relationships between proinflammatory cytokines and hormone levels, pain intensity, and psychological distress in a sample of 34 premenopausal and postmenopausal women with fibromyalgia. Our results indicated significant relationships between interleukin-8 and ratings of pain catastrophizing (r=0.555, P<0.05), pain anxiety (r=0.559, P<0.05), and depression (r=0.551, P<0.05) for postmenopausal women but not premenopausal women (r,0.20 in all cases). Consistent with previous studies, ratios of interleukin-6 to interleukin-10 were significantly lower in individuals with greater levels of depressive symptoms (r=-0.239, P<0.05). Contrary to previous research, however, dehydroepiandrosterone sulfate did not correlate with pain intensity or psychological or biological variables. The results of the current study highlight the importance of psychological functioning and milestones of aging in the examination of inflammatory processes in fibromyalgia.

Abstract

While reducing the burden of brain disorders remains a top priority of organizations like the World Health Organization and National Institutes of Health, the development of novel, safe and effective treatments for brain disorders has been slow. In this paper, we describe the state of the science for an emerging technology, real time functional magnetic resonance imaging (rtfMRI) neurofeedback, in clinical neurotherapeutics. We review the scientific potential of rtfMRI and outline research strategies to optimize the development and application of rtfMRI neurofeedback as a next generation therapeutic tool. We propose that rtfMRI can be used to address a broad range of clinical problems by improving our understanding of brain-behavior relationships in order to develop more specific and effective interventions for individuals with brain disorders. We focus on the use of rtfMRI neurofeedback as a clinical neurotherapeutic tool to drive plasticity in brain function, cognition, and behavior. Our overall goal is for rtfMRI to advance personalized assessment and intervention approaches to enhance resilience and reduce morbidity by correcting maladaptive patterns of brain function in those with brain disorders.

Abstract

Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long-term studies, and head-to-head comparisons among different interventional and noninterventional treatments.

Abstract

Functional magnetic resonance imaging (fMRI) is a technique that uses blood oxygen-level-dependent (BOLD) signals to elucidate discrete areas of neuronal activity. Despite the significant number of fMRI human brain studies, few researchers have applied fMRI technology to investigating neuronal activity within the human spinal cord. Our study goals were to demonstrate that fMRI could reveal the following: (i) appropriate somatotopic activations in response to noxious stimuli in the deep and superficial dorsal horn of the human cervical spinal cord, and (ii) lateralization of fMRI activations in response to noxious stimulation in the right and left upper extremity. We subjected healthy participants to noxious stimulation during fMRI scans. Using a spiral in-out image sequence and retrospective correction for physiologic noise, we demonstrated that fMRI can create high-resolution, neuronal activation maps of the human cervical spinal cord. During nociceptive stimulation of all 4 sites (left deltoid, right deltoid, left thenar eminence and right thenar eminence), we found ipsilateral dorsal horn activation. Stimulation of the deltoid activated C5, whereas stimulation of the thenar eminence activated C6. Our study contributes to creating an objective analysis of pain transmission; other investigators can use these results to further study central nervous system changes that occur in patients with acute and chronic pain.

Abstract

Approximately 10% of patients following a variety of surgeries develop chronic postsurgical pain. Reducing chronic postoperative pain is especially important to reconstructive surgeons because common operations such as breast and limb reconstruction have even higher risk for developing chronic postsurgical pain. Animal studies of posttraumatic nerve injury pain demonstrate that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviors-so called "preventative analgesia." In animal models, perineural local anesthetic, systemic intravenous local anesthetic, perineural clonidine, systemic gabapentin, systemic tricyclic antidepressants, and minocycline have each been shown to reduce pain behaviors days to weeks after treatment. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain. Recent clinical trial data show that there is an opportunity during the perioperative period to dramatically reduce the incidence and severity of chronic postsurgical pain. The surgeon, working with the anesthesiologist, has the ability to modify both early and chronic postoperative pain by implementing an evidence-based preventative analgesia plan.

Abstract

Approximately 10% of patients following a variety of surgeries develop chronic postsurgical pain. Reducing chronic postoperative pain is especially important to reconstructive surgeons because common operations such as breast and limb reconstruction have even higher risk for developing chronic postsurgical pain. Animal studies of posttraumatic nerve injury pain demonstrate that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviors-so called "preventative analgesia." In animal models, perineural local anesthetic, systemic intravenous local anesthetic, perineural clonidine, systemic gabapentin, systemic tricyclic antidepressants, and minocycline have each been shown to reduce pain behaviors days to weeks after treatment. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain. Recent clinical trial data show that there is an opportunity during the perioperative period to dramatically reduce the incidence and severity of chronic postsurgical pain. The surgeon, working with the anesthesiologist, has the ability to modify both early and chronic postoperative pain by implementing an evidence-based preventative analgesia plan.

Abstract

To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue.Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain.When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported.The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.

Abstract

Use of opioid analgesics for pain management has increased dramatically over the past decade, with corresponding increases in negative sequelae including overdose and death. There is currently no well-validated objective means of accurately identifying patients likely to experience good analgesia with low side effects and abuse risk prior to initiating opioid therapy. This paper discusses the concept of data-based personalized prescribing of opioid analgesics as a means to achieve this goal. Strengths, weaknesses, and potential synergism of traditional randomized placebo-controlled trial (RCT) and practice-based evidence (PBE) methodologies as means to acquire the clinical data necessary to develop validated personalized analgesic-prescribing algorithms are overviewed. Several predictive factors that might be incorporated into such algorithms are briefly discussed, including genetic factors, differences in brain structure and function, differences in neurotransmitter pathways, and patient phenotypic variables such as negative affect, sex, and pain sensitivity. Currently available research is insufficient to inform development of quantitative analgesic-prescribing algorithms. However, responder subtype analyses made practical by the large numbers of chronic pain patients in proposed collaborative PBE pain registries, in conjunction with follow-up validation RCTs, may eventually permit development of clinically useful analgesic-prescribing algorithms.Current research is insufficient to base opioid analgesic prescribing on patient characteristics. Collaborative PBE studies in large, diverse pain patient samples in conjunction with follow-up RCTs may permit development of quantitative analgesic-prescribing algorithms that could optimize opioid analgesic effectiveness and mitigate risks of opioid-related abuse and mortality.

Abstract

We discuss the emerging translational tools for the study of acupuncture analgesia with a focus on psychophysical methods. The gap between animal mechanistic studies and human clinical trials of acupuncture analgesia calls for effective translational tools that bridge neurophysiological data with meaningful clinical outcomes. Temporal summation (TS) and conditioned pain modulation (CPM) are two promising tools yet to be widely utilized. These psychophysical measures capture the state of the ascending facilitation and the descending inhibition of nociceptive transmission, respectively. We review the basic concepts and current methodologies underlying these measures in clinical pain research, and illustrate their application to research on acupuncture analgesia. Finally, we highlight the strengths and limitations of these research methods and make recommendations on future directions. The appropriate addition of TS and CPM to our current research armamentarium will facilitate our efforts to elucidate the central analgesic mechanisms of acupuncture in clinical populations.

Abstract

Temporal summation (TS) refers to the increased perception of pain with repetitive noxious stimuli. It is a behavioral correlate of wind-up, the spinal facilitation of recurring C-fiber stimulation. In order to utilize TS in clinical pain research, it is important to characterize TS in a wide range of individuals and to establish its test-retest reliability. Building on a fixed-parameter protocol, we developed an individually adjusted protocol to broadly capture thermally generated TS. We then examined the test-retest reliability of TS within-day (intertrial intervals ranging from 2 to 30 minutes) and between-days (intersession interval of 7 days). We generated TS-like effects in 19 of the 21 participants. Strong correlations were observed across all trials over both days (intraclass correlation [ICC] [A, 10] = .97, 95% confidence level [CL] = .94-.99) and across the initial trials between days (ICC [A, 1] = .83, 95% CL = .58-.93). Repeated measures mixed-effects modeling demonstrated no significant within-day variation and only a small (5 out of 100 points) between-day variation. Finally, a Bland-Altman analysis suggested that TS is reliable across the range of observed scores. Without intervention, thermally-generated TS is generally stable within day and between days.Our study introduces a new strategy to generate thermal TS in a high proportion of individuals. This study confirms the test-retest reliability of thermal TS, supporting its use as a consistent behavioral correlate of central nociceptive facilitation.

Abstract

A patient's response to treatment may be influenced by the expectations that the patient has before initiating treatment. In the context of clinical trials, the influence of participant expectancy may blur the distinction between real and sham treatments, reducing statistical power to detect specific treatment effects. There is therefore a need for a tool that prospectively predicts expectancy effects on treatment outcomes across a wide range of treatment modalities.To help assess expectancy effects, we created the Stanford Expectations of Treatment Scale (SETS): an instrument for measuring positive and negative treatment expectancies. Internal reliability of the instrument was tested in Study 1. Criterion validity of the instrument (convergent, discriminant, and predictive) was assessed in Studies 2 and 3.The instrument was developed using 200 participants in Study 1. Reliability and validity assessments were made with an additional 423 participants in Studies 2 and 3.The final six-item SETS contains two subscales: positive expectancy (α = 0.81-0.88) and negative expectancy (α = 0.81-0.86). The subscales predict a significant amount of outcome variance (between 12% and 18%) in patients receiving surgical and pain interventions. The SETS is simple to administer, score, and interpret.The SETS may be used in clinical trials to improve statistical sensitivity for detecting treatment differences or in clinical settings to identify patients with poor treatment expectancies.

Abstract

Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery.Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done.Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self-perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%-87%) reduction in the rate of opioid cessation after surgery (P = 0.0009). Additionally, each 1-point increase (on a 4-point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%-71%) reduction in the rate of opioid cessation (P = 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%-58%) reduction in the rate of opioid cessation (P = 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity.Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity.

Abstract

Current views recognize the brain as playing a pivotal role in the arising and maintenance of pain experience. Real-time fMRI (rtfMRI) feedback is a potential tool for pain modulation that directly targets the brain with the goal of restoring regulatory function. Though still relatively new, rtfMRI is a rapidly developing technology that has evolved in the last 15 years from simple proof of concept experiments to demonstrations of learned control of single and multiple brain areas. Numerous studies indicate rtfMRI feedback assisted control over specific brain areas may have applications including mood regulation, language processing, neurorehabilitation in stroke, enhancement of perception and learning, and pain management. We discuss in detail earlier work from our lab in which rtfMRI feedback was used to train both healthy controls and chronic pain patients to modulate anterior cingulate cortex (ACC) activation for the purposes of altering pain experience. Both groups improved in their ability to control ACC activation and modulate their pain with rtfMRI feedback training. Furthermore, the degree to which participants were able to modulate their pain correlated with the degree of control over ACC activation. We additionally review current advances in rtfMRI feedback, such as real-time pattern classification, that bring the technology closer to more comprehensive control over neural function. Finally, remaining methodological questions concerning the further development of rtfMRI feedback and its implications for the future of pain research are also discussed.

Abstract

The qualities of chronic neuropathic pain (NeP) may be informative about the different mechanisms of pain. We previously developed a 2-factor model of NeP that described an underlying structure among sensory descriptors on the Short-Form McGill Pain Questionnaire. The goal of this study was to confirm the correlated 2-factor model of NeP. Individual descriptive scores from the Short-Form McGill Pain Questionnaire were analyzed. Confirmatory factor analysis was used to test a correlated 2-factor model. Factor 1 (stabbing pain) was characterized by high loadings on stabbing, sharp, and shooting sensory items; factor 2 (heavy pain) was characterized by high loadings on heavy, gnawing, and aching items. Results of the confirmatory factor analysis strongly supported the correlated 2-factor model.This article validates a model that describes the qualities of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. These data suggest that specific pain qualities may be associated with pain mechanisms or may be useful for predicting treatment response.

Abstract

Cognitive strategies are a set of psychologic behaviors used to modulate one's perception or interpretation of a sensation or situation. Although the effectiveness of each cognitive strategy seems to differ between individuals, they are commonly used clinically to help patients with chronic pain cope with their condition. The neural basis of commonly used cognitive strategies is not well understood. Understanding the neural correlates that underlie these strategies will enhance understanding of the analgesic network of the brain and the cognitive modulation of pain.The current study examines patterns of brain activation during two common cognitive strategies, external focus of attention and reappraisal, in patients with chronic pain using functional magnetic resonance imaging.Behavioral results revealed interindividual variability in the effectiveness of one strategy versus another in the patients. Functional magnetic resonance imaging revealed distinct patterns of activity when the two strategies were used. During external focus of attention, activity was observed mainly in cortical areas including the postcentral gyrus, inferior parietal lobule, middle occipital gyrus, and precentral gyrus. The use of reappraisal evoked activity in the thalamus and amygdala in addition to cortical regions. Only one area, the postcentral gyrus, was observed to be active during both strategies.The results of this study suggest that different cognitive behavioral strategies recruit different brain regions to perform the same task: pain modulation.

Abstract

Pain often exists in the absence of observable injury; therefore, the gold standard for pain assessment has long been self-report. Because the inability to verbally communicate can prevent effective pain management, research efforts have focused on the development of a tool that accurately assesses pain without depending on self-report. Those previous efforts have not proven successful at substituting self-report with a clinically valid, physiology-based measure of pain. Recent neuroimaging data suggest that functional magnetic resonance imaging (fMRI) and support vector machine (SVM) learning can be jointly used to accurately assess cognitive states. Therefore, we hypothesized that an SVM trained on fMRI data can assess pain in the absence of self-report. In fMRI experiments, 24 individuals were presented painful and nonpainful thermal stimuli. Using eight individuals, we trained a linear SVM to distinguish these stimuli using whole-brain patterns of activity. We assessed the performance of this trained SVM model by testing it on 16 individuals whose data were not used for training. The whole-brain SVM was 81% accurate at distinguishing painful from non-painful stimuli (p<0.0000001). Using distance from the SVM hyperplane as a confidence measure, accuracy was further increased to 84%, albeit at the expense of excluding 15% of the stimuli that were the most difficult to classify. Overall performance of the SVM was primarily affected by activity in pain-processing regions of the brain including the primary somatosensory cortex, secondary somatosensory cortex, insular cortex, primary motor cortex, and cingulate cortex. Region of interest (ROI) analyses revealed that whole-brain patterns of activity led to more accurate classification than localized activity from individual brain regions. Our findings demonstrate that fMRI with SVM learning can assess pain without requiring any communication from the person being tested. We outline tasks that should be completed to advance this approach toward use in clinical settings.

Abstract

Chronic opioid exposure is known to produce neuroplastic changes in animals; however, it is not known if opioids used over short periods of time and at analgesic dosages can similarly change brain structure in humans. In this longitudinal, magnetic resonance imaging study, 10 individuals with chronic low back pain were administered oral morphine daily for 1 month. High-resolution anatomical images of the brain were acquired immediately before and after the morphine administration period. Regional changes in gray matter volume were assessed on the whole brain using tensor-based morphometry, and those significant regional changes were then independently tested for correlation with morphine dosage. Thirteen regions evidenced significant volumetric change, and degree of change in several of the regions was correlated with morphine dosage. Dosage-correlated volumetric decrease was observed primarily in the right amygdala. Dosage-correlated volumetric increase was seen in the right hypothalamus, left inferior frontal gyrus, right ventral posterior cingulate, and right caudal pons. Follow-up scans that were conducted an average of 4.7 months after cessation of opioids demonstrated many of the morphine-induced changes to be persistent. In a separate study, 9 individuals consuming blinded placebo capsules for 6 weeks evidenced no significant morphologic changes over time. The results add to a growing body of literature showing that opioid exposure causes structural and functional changes in reward- and affect-processing circuitry. Morphologic changes occur rapidly in humans during new exposure to prescription opioid analgesics. Further research is needed to determine the clinical impact of those opioid-induced gray matter changes.

Abstract

Describe the first reported human intrathecal (IT) botulinum toxin injection.Case report.We report here the sequelae to an unintended IT injection of botulinum toxin type B (BTB) in a 60-year-old woman with chronic back pain.Following the IT administration of BTB, the patient experienced the onset of symmetric ascending stocking distribution painful dysesthesias, which persisted for approximately 6 months before receding. Objective neurologic deficits were not appreciated, and analgesic effects were prominently absent.Analgesic actions of botulinum toxins in animals and in humans have led to speculation that IT botulinum toxin might exert significant analgesic effects. The unusual and unexpected subsequent clinical course, neurologic sequelae, dysesthesias, and absence of analgesia suggest that botulinum toxin will not be a therapeutic modality to treat pain as proposed by those studying botulinum toxin in animal models.

Abstract

The clinical diagnosis of Complex Regional Pain Syndrome (CRPS) is a dichotomous (yes/no) categorization necessary for clinical decision-making. However, such dichotomous diagnostic categories do not convey an individual's subtle and temporal gradations in severity of the condition, and have poor statistical power when used as an outcome measure in research. This study evaluated the validity and potential utility of a continuous type score to index severity of CRPS. Psychometric and medical evaluations were conducted in 114 CRPS patients and 41 non-CRPS neuropathic pain patients. Based on the presence/absence of 17 clinically-assessed signs and symptoms of CRPS, an overall CRPS Severity Score (CSS) was derived. The CSS discriminated well between CRPS and non-CRPS patients (p

Abstract

The early stages of a new romantic relationship are characterized by intense feelings of euphoria, well-being, and preoccupation with the romantic partner. Neuroimaging research has linked those feelings to activation of reward systems in the human brain. The results of those studies may be relevant to pain management in humans, as basic animal research has shown that pharmacologic activation of reward systems can substantially reduce pain. Indeed, viewing pictures of a romantic partner was recently demonstrated to reduce experimental thermal pain. We hypothesized that pain relief evoked by viewing pictures of a romantic partner would be associated with neural activations in reward-processing centers. In this functional magnetic resonance imaging (fMRI) study, we examined fifteen individuals in the first nine months of a new, romantic relationship. Participants completed three tasks under periods of moderate and high thermal pain: 1) viewing pictures of their romantic partner, 2) viewing pictures of an equally attractive and familiar acquaintance, and 3) a word-association distraction task previously demonstrated to reduce pain. The partner and distraction tasks both significantly reduced self-reported pain, although only the partner task was associated with activation of reward systems. Greater analgesia while viewing pictures of a romantic partner was associated with increased activity in several reward-processing regions, including the caudate head, nucleus accumbens, lateral orbitofrontal cortex, amygdala, and dorsolateral prefrontal cortex--regions not associated with distraction-induced analgesia. The results suggest that the activation of neural reward systems via non-pharmacologic means can reduce the experience of pain.

Abstract

Current IASP diagnostic criteria for CRPS have low specificity, potentially leading to overdiagnosis. This validation study compared current IASP diagnostic criteria for CRPS to proposed new diagnostic criteria (the "Budapest Criteria") regarding diagnostic accuracy. Structured evaluations of CRPS-related signs and symptoms were conducted in 113 CRPS-I and 47 non-CRPS neuropathic pain patients. Discriminating between diagnostic groups based on presence of signs or symptoms meeting IASP criteria showed high diagnostic sensitivity (1.00), but poor specificity (0.41), replicating prior work. In comparison, the Budapest clinical criteria retained the exceptional sensitivity of the IASP criteria (0.99), but greatly improved upon the specificity (0.68). As designed, the Budapest research criteria resulted in the highest specificity (0.79), again replicating prior work. Analyses indicated that inclusion of four distinct CRPS components in the Budapest Criteria contributed to enhanced specificity. Overall, results corroborate the validity of the Budapest Criteria and suggest they improve upon existing IASP diagnostic criteria for CRPS.

Abstract

Myofascial pain of the temporomandibular region (M-TMD) is a common, but poorly understood chronic disorder. It is unknown whether the condition is a peripheral problem, or a disorder of the central nervous system (CNS). To investigate possible CNS substrates of M-TMD, we compared the brain morphology of 15 women with M-TMD to that of 15 age- and gender-matched healthy controls. High-resolution structural brain and brainstem scans were carried out using magnetic resonance imaging (MRI), and data were analyzed using a voxel-based morphometry approach. The M-TMD group evidenced decreased or increased gray matter volume compared to controls in several areas of the trigeminothalamocortical pathway, including brainstem trigeminal sensory nuclei, the thalamus, and the primary somatosensory cortex. In addition, M-TMD individuals showed increased gray matter volume compared to controls in limbic regions such as the posterior putamen, globus pallidus, and anterior insula. Within the M-TMD group, jaw pain, pain tolerance, and pain duration were differentially associated with brain and brainstem gray matter volume. Self-reported pain severity was associated with increased gray matter in the rostral anterior cingulate cortex and posterior cingulate. Sensitivity to pressure algometry was associated with decreased gray matter in the pons, corresponding to the trigeminal sensory nuclei. Longer pain duration was associated with greater gray matter in the posterior cingulate, hippocampus, midbrain, and cerebellum. The pattern of gray matter abnormality found in M-TMD individuals suggests the involvement of trigeminal and limbic system dysregulation, as well as potential somatotopic reorganization in the putamen, thalamus, and somatosensory cortex.

Abstract

The study of functionally relevant biological effects of serotonin transporter gene promoter region (5-HTTLPR) polymorphisms is especially important given the current controversy about the clinical relevance of these polymorphisms. Here we report an intrinsic immunobiological difference between individuals carrying two short (SS) versus long (LL) 5-HTTLPR alleles, that is observed in healthy subjects reporting low exposure to life stress. Given that 5-HTTLPR polymorphisms are thought to influence susceptibility to depression and are associated with robust neurobiological effects, that depression is associated with higher pro-inflammatory and lower anti-inflammatory cytokines, and that acute stressors increase circulating concentrations of pro-inflammatory cytokines, we hypothesized that compared to LL individuals, SS individuals may show a pro-inflammatory bias under resting conditions and/or during stress. 15 LL and 11 SS individuals participated in the Trier Social Stress Test (TSST). Serum IL-6 and IL-10 were quantified at baseline and 30, 60, 90, and 120min after beginning the 20-min stress test. Compared to LL individuals, SS individuals showed a higher IL-6/IL-10 ratio at baseline and during stress. Importantly, this pro-inflammatory bias was observed despite both groups being healthy, reporting similar intensities of stress and negative emotionality during the TSST, and reporting similar low exposures to early and recent life stress. To our knowledge, this is the first report of a pro-inflammatory bias/phenotype in individuals carrying the SS genotype of 5-HTTLPR. Thus, healthy SS individuals may be chronically exposed to a pro-inflammatory physiological burden under resting and stress conditions, which could increase their vulnerability to disorders like depression and other diseases that can be facilitated/exacerbated by a chronic pro-inflammatory state.

Abstract

Chronic neuropathic pain is a prevalent problem that eludes cure and adequate treatment. The persistence of intense and aversive symptoms, inadequacy of available treatments, and impact of such pain on all aspects of functioning underscore the important role of several psychosocial factors in causing, maintaining, and amplifying the perception of pain severity, coping adequacy, adaptation, impaired physical function, and emotional distress responses. Moreover, these factors have an influential role in response to treatment recommendations. In this article, we (1) review the prevalence and nature of emotional distress, (2) describe and propose methods for screening and comprehensive psychosocial assessment, and (3) review evidence supporting the potential complementary role of psychosocial treatments of patients with chronic pain. The cognitive-behavioral perspective and treatment approach are emphasized because the greatest amount of evidence supports their benefits. Published results of psychological treatments are modest; however, the same indictment can be placed on currently available pharmacological, medical, and interventional treatments for patients with chronic pain. We note the limited research on the effectiveness of psychological treatment specifically applied to patients with chronic neuropathic pain but suggest that it is reasonable to extrapolate from successful trials in other types of chronic pain. Furthermore, psychological approaches should not be viewed as alternatives but rather should be integrated as part of a comprehensive approach to the treatment of patients with chronic neuropathic pain.

Abstract

The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel alpha(2)-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.

Abstract

Inguinal hernia repair is associated with a high incidence of chronic postsurgical pain. This pain may be caused by injury to the iliohypogastric, ilioinguinal, or genitofemoral nerves. It is often difficult to identify the specific source of the pain, in part, because these nerves are derived from overlapping nerve roots and closely colocalize in the area of surgery. It is therefore technically difficult to selectively block these nerves individually proximal to the site of surgical injury. In particular, the genitofemoral nerve is retroperitoneal before entering the inguinal canal, a position that puts anterior approaches to the proximal nerve at risk of transgressing into the peritoneum. We report a computed tomography (CT)-guided transpsoas technique to selectively block the genitofemoral nerve for both diagnostic and therapeutic purposes while avoiding injury to the nearby ureter and intestines.A 39-year-old woman with chronic lancinating right groin pain after inguinal hernia repair underwent multiple pharmacologic interventions and invasive procedures without relief. Using CT and Stimuplex nerve stimulator guidance, the genitofemoral nerve was localized on the anterior surface of the psoas muscle and a diagnostic block with local anesthetic block was performed. The patient had immediate relief of her symptoms for 36 hours, confirming the diagnosis of genitofemoral neuralgia. She subsequently underwent CT-guided radiofrequency and phenol ablation of the genitofemoral nerve but has not achieved long-term analgesia.CT-guided transpsoas genitofemoral nerve block is a viable option for safely and selectively blocking the genitofemoral nerve for diagnostic or therapeutic purposes proximal to injury caused by inguinal surgery.

Abstract

To assess the benefits of subcutaneous injection of botulinum toxin A (BTX-A) for the treatment of postherpetic neuralgia (PHN).We investigated the therapeutic benefits of BTX-A in subjects with PHN in a randomized, double-blind, placebo-controlled study. Sixty subjects with PHN were randomly and evenly distributed into BTX-A, lidocaine, and placebo groups.After randomization, one of the following solutions was injected subcutaneously in the affected dermatome: 5u/mL BTX-A, 0.5% lidocaine, or 0.9% saline (placebo). Visual analog scale (VAS) pain and sleeping time (hours) were evaluated at the time of pretreatment, day 1, day 7, and 3 months posttreatment. Opioid usage was calculated at day 7 and 3 months posttreatment. Compared with pretreatment, VAS pain scores decreased at day 7 and 3 months posttreatment in all three groups (P<0.01). However, the VAS pain scores of the BTX-A group decreased more significantly compared with lidocaine and placebo groups at day 7 and 3 months posttreatment (P<0.01). Sleep time (hours) had improved at day 7 and at 3 months compared with pretreatment in all three groups, but the BTX-A group improved more significantly compared with lidocaine and placebo groups (P<0.01). The percent of subjects using opioids posttreatment in the BTX-A group was the lowest (21.1%) compared with the lidocaine (52.6%) and placebo (66.7%) groups (P<0.01).Subcutaneous administration of BTX-A significantly decreased pain in PHN and reduced opioid use compared with lidocaine and placebo at day 7 and 3 months post-treatment. It also increased subjects' sleep times.

Abstract

To evaluate the effectiveness of acupuncture in treating symptoms associated with myofascial pain of the jaw muscles.Twenty-eight subjects over the age of 18 and diagnosed with chronic myofascial pain of the jaw muscles were randomized to receive real (n = 16) or sham (n = 12) acupuncture. Prior to treatment, each subject clenched his or her teeth for 2 minutes. Acupuncture or sham acupuncture was then administered at the Hegu large intestine 4 (LI4) acupoint for 15 minutes. Real acupuncture was given by penetrating the needle through a sticky foam pad at the acupoint. Sham acupuncture was conducted by pricking the skin, without penetration, with a shortened, blunted acupuncture needle through a foam pad placed away from the acupoint. General head and neck pain ratings were obtained before and after treatment on a numerical rating scale. A mechanical pain stimulus on the masseter muscle was given before and after treatment and rated on a visual analog scale to measure pain tolerance level. Paired t tests were performed to detect significant changes in pain levels.Subjects receiving real acupuncture experienced a significant reduction in jaw pain (P = .04), jaw/face tightness (P = .04), and neck pain (P = .04), and a significant increase in pain tolerance of the masseter muscle (P = .001). Subjects were not able to determine whether they received real or sham acupuncture (P = .69). No significant pain reductions were observed in the sham acupuncture group.A single acupuncture session using one acupoint at Hegu large intestine 4 significantly reduced most myofascial pain endpoints when compared to sham acupuncture.

Abstract

Fibromyalgia is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation. In this pilot clinical trial, we tested the effectiveness of low-dose naltrexone in treating the symptoms of fibromyalgia.Participants completed a single-blind, crossover trial with the following time line: baseline (2 weeks), placebo (2 weeks), drug (8 weeks), and washout (2 weeks).Ten women meeting criteria for fibromyalgia and not taking an opioid medication.Naltrexone, in addition to antagonizing opioid receptors on neurons, also inhibits microglia activity in the central nervous system. At low doses (4.5 mg), naltrexone may inhibit the activity of microglia and reverse central and peripheral inflammation.Participants completed reports of symptom severity everyday, using a handheld computer. In addition, participants visited the lab every 2 weeks for tests of mechanical, heat, and cold pain sensitivity.Low-dose naltrexone reduced fibromyalgia symptoms in the entire cohort, with a greater than 30% reduction of symptoms over placebo. In addition, laboratory visits showed that mechanical and heat pain thresholds were improved by the drug. Side effects (including insomnia and vivid dreams) were rare, and described as minor and transient. Baseline erythrocyte sedimentation rate predicted over 80% of the variance in drug response. Individuals with higher sedimentation rates (indicating general inflammatory processes) had the greatest reduction of symptoms in response to low-dose naltrexone.We conclude that low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia.

Abstract

Emotional-affective and cognitive dimensions of pain are less well understood than nociceptive and nocifensive components, but the forebrain is believed to play an important role. Recent evidence suggests that subcortical and cortical brain areas outside the traditional pain processing network contribute critically to emotional-affective responses and cognitive deficits related to pain. These brain areas include different nuclei of the amygdala and certain prefrontal cortical areas. Their roles in various aspects of pain will be discussed. Biomarkers of cortical dysfunction are being identified that may evolve into therapeutic targets to modulate pain experience and improve pain-related cognitive impairment. Supporting data from preclinical studies in neuropathic pain models will be presented. Neuroimaging analysis provides evidence for plastic changes in the pain processing brain network. Results of clinical studies in neuropathic pain patients suggest that neuroimaging may help determine mechanisms of altered brain functions in pain as well as monitor the effects of pharmacologic interventions to optimize treatment in individual patients. Recent progress in the analysis of higher brain functions emphasizes the concept of pain as a multidimensional experience and the need for integrative approaches to determine the full spectrum of harmful or protective neurobiological changes in pain.

Abstract

Complex regional pain syndrome is a refractory pain condition with few tested therapies. We hypothesized that botulinum toxin A (BTA) would prolong analgesia after sympathetic blocks in patients with complex regional pain syndrome. We compared the duration of standard lumbar sympathetic block (LSB) with bupivacaine to LSB with bupivacaine and BTA in nine patients with refractory complex regional pain syndrome. Median time to analgesic failure was 71 (95% confidence interval, 12-253) days after LSB with BTA compared with fewer than 10 days (95% confidence interval, 0-12) after standard LSB (log-rank, p < 0.02). BTA profoundly prolonged the analgesia from sympathetic block in this preliminary study.

Abstract

Pain is a difficult outcome to measure due to its multifaceted and subjective nature. The need for selecting proper outcome measures is high because of the increasing demand for scientifically valid demonstrations of treatment efficacy. This article discusses some basic topics in the measurement of pain outcomes and addresses issues such as statistical versus clinical significance, daily home data collection, appropriate length of outcome measurement packets, and the possibility of objective pain measurements. This article also reviews some of the more commonly used tools for measuring pain and pain-related disability. By selecting the proper tools and employing them correctly, we can obtain highly reliable and valid measures of pain outcomes in research and clinical care.

Abstract

Currently, notalgia paresthetica (NP) is a poorly-understood condition diagnosed on the basis of pruritus, pain, or both, in the area medial to the scapula and lateral to the thoracic spine. It has been proposed that NP is caused by degenerative changes to the T2-T6 vertebrae, genetic disposition, or nerve entrapment of the posterior rami of spinal nerves arising at T2-T6. Despite considerable research, the etiology of NP remains unclear, and a multitude of different treatment modalities have correspondingly met with varying degrees of success. Here we demonstrate that NP can be caused by long thoracic nerve injury leading to serratus anterior dysfunction, and that electrical muscle stimulation (EMS) of the serratus anterior can successfully and conservatively treat NP. In four cases of NP with known injury to the long thoracic nerve we performed transcutaneous EMS to the serratus anterior in an area far lateral to the site of pain and pruritus, resulting in significant and rapid pain relief. These findings are the first to identify long thoracic nerve injury as a cause for notalgia paresthetica and electrical muscle stimulation of the serratus anterior as a possible treatment, and we discuss the implications of these findings on better diagnosing and treating notalgia paresthetica.

Abstract

One potential consequence of chronic opioid analgesic administration is a paradoxical increase of pain sensitivity over time. Little scientific attention has been given to how cessation of opioid medication affects the hyperalgesic state. In this study, we examined the effects of opioid tapering on pain sensitivity in chronic pain patients.Twelve chronic pain patients on long-term opioid analgesic treatment were observed in a 7- to 14-day inpatient pain rehabilitation program, with cold pain tolerance assessed at admission and discharge. The majority of participants were completely withdrawn from their opioids during their stay.We hypothesized that those patients with the greatest reduction in daily opioid use would show the greatest increases in pain tolerance, as assessed by a cold pressor task.A linear regression revealed that the amount of opioid medication withdrawn was a significant predictor of pain tolerance changes, but not in the direction hypothesized. Greater opioid reduction was associated with decreased pain tolerance. This reduction of pain tolerance was not associated with opioid withdrawal symptoms or changes in general pain.These findings suggest that the withdrawal of opioids in a chronic pain sample leads to an acute increase in pain sensitivity.

Abstract

Humans possess a remarkable capacity to understand the suffering of others. Cognitive neuroscience theories of empathy suggest that this capacity is supported by 'shared representations' of self and other. Consistent with this notion, a number of studies have found that perceiving others in pain and experiencing pain oneself recruit overlapping neural systems. Perception of pain in each of these conditions, however, may also cause unique patterns of activation, that may reveal more about the processing steps involved in each type of pain. To address this issue, we examined neural activity while participants experienced heat pain and watched videos of other individuals experiencing injuries. Results demonstrated (i) that both tasks activated anterior cingulate cortex and anterior insula, consistent with prior work; (ii) whereas self-pain activated anterior and mid insula regions implicated in interoception and nociception, other pain activated frontal, premotor, parietal and amygdala regions implicated in emotional learning and processing social cues; and (iii) that levels of trait anxiety correlated with activity in rostral lateral prefrontal cortex during perception of other pain but not during self-pain. Taken together, these data support the hypothesis that perception of pain in self and other, while sharing some neural commonalities, differ in their recruitment of systems specifically associated with decoding and learning about internal or external cues.

Abstract

Pulsed radiofrequency (PRF), a technology related to continuous radiofrequency, is unique in that it provides pain relief without causing significant damage to nervous tissue. The mechanism by which PRF controls pain is unclear, but it may involve a temperature-independent pathway mediated by a rapidly changing electrical field. Although much anecdotal evidence exists in favor of PRF, there are few quality studies substantiating its utility.

Abstract

Rapidly developing, non-invasive, neuroimaging methods provide increasingly detailed structural and functional information about the nervous system, helping advance our understanding of pain processing, chronic pain conditions and the mechanisms of analgesia. However, effective treatment for many chronic pain conditions remains a large, unmet medical need. Neuroimaging techniques may enhance our understanding of why currently available analgesics are ineffective for so many patients and aid in identifying new neural targets for pharmacological interventions of pain. This review examines how neuroimaging has enhanced our understanding of the mechanisms of chronic pain, the neural correlates of pharmacological modulation of pain, and the role of neuroimaging in analgesic development. Rather than focusing on one method, we discuss the advantages and limitations of several techniques that may each serve a unique role in aiding drug development, and we discuss current issues that exist in the design and implementation of pharmacological neuroimaging studies. Particularly, experimental design must be carefully considered as there are limitations in terms of the pharmacokinetics of the drug of interest as well as in respect to the capabilities of the neuroimaging method in use. Finally, we identify future directions including novel approaches that may also play a role in furthering our knowledge of the neural basis of analgesia. In the future, neuroimaging will certainly impact the methodology of analgesic drug development as it may lead to quicker and more efficient methods of evaluating the neural modulation of chronic pain.

Abstract

The proportion of chronic pain patients with suspected neuropathic pain who will have clinically meaningful pain relief with intravenous (IV) lidocaine and the clinical characteristics that identify these patients have not been described previously.We conducted a cohort study of 99 patients who underwent IV lidocaine infusions for suspected neuropathic pain. An 11-point Numerical Rating Score (NRS) of pain intensity was recorded at the beginning and end of each infusion. A predefined literature-based criteria for "clinically meaningful" reductions in pain score was used to classify patients as responders or nonresponders. Multivariate logistic regression was used to determine clinical variables that predicted an increased likelihood of being a lidocaine responder.The mean reduction in NRS during lidocaine infusions was 2.34 (95% confidence interval 2.83-1.85, P<0.001). Forty-two percent of patients (95% confidence interval 32.5%-52.8%) had NRS reductions of 30% or greater and met the predefined criteria as lidocaine responders. Univariate and multivariate analyses indicated that advancing age and pain severity significantly increased the odds of being a lidocaine responder. Controlled for all other factors, each decade of advancing age increased the odds of being a lidocaine responder by 36%. Each 1-point increase, on an 11-point scale of baseline pain severity, increased the odds of being a lidocaine responder by 29%.IV lidocaine effectively reduces pain in a minority of patients suspected of having neuropathic pain. Pain severity and patient age can be used to target therapy to those most likely to respond.

Abstract

The ability to empathize with the suffering of others is critical for maintaining relationships and engaging in prosocial behavior. Recently, a series of studies have demonstrated that while watching other people experience pain (other pain), participants engage the anterior insula (AI) and anterior cingulate cortex (ACC), brain regions involved in the direct experience of pain (self pain). Here we test the hypothesis that common activity in ACC and AI may reflect the operation of distinct but overlapping networks of regions that support perception of self or other pain. To address this possibility, we scanned participants using fMRI while they received noxious thermal stimulation (self pain) or watched short videos of other people sustaining painful injuries (other pain). We isolated overlapping regions for self and other pain in the ACC and AI and then used them as seed regions for two kinds of functional connectivity analyses. These analyses identified areas whose activity co-varied with ACC and AI activity during self or other pain either across time (intra-individual connectivity) or across participants (inter-individual connectivity). Both connectivity analyses identified clusters in the midbrain and periaqueductal gray with greater connectivity to the AI during self pain as opposed to other pain. The opposite pattern was found in the dorsal medial prefrontal cortex, that showed greater connectivity to the ACC and AI during other pain than during self pain using both types of analysis. Intra-individual connectivity analyses also revealed regions in the superior temporal sulcus, posterior cingulate, and precuneus that became more connected to ACC during other pain as compared to self pain. Together, these data demonstrated that regions showing similar activity during self and other pain may nonetheless be part of distinct functional networks. These networks could not have been detected in prior work that examined overlap between self and other pain in terms of average activity, but not connectivity.

Abstract

Ilioinguinal neuropathy is a rare but disabling condition. The condition may arise spontaneously or in the setting of pelvic surgery. To date, most therapeutic options have been limited to neuropathic pain medications, anti-inflammatory medications, nerve blocks with local anesthetics, or neurectomy. Long-term results of non-surgical interventions are fair at best. We present a case of chronic ilioinguinal neuropathy treated with pulsed radiofrequency.To examine the efficacy of pulsed radiofrequency (PRF) lesioning on pain in ilioinguinal neuropathy.A 58-year old man with chronic ilioinguinal neuropathy was treated with PRF and was followed for 3 months.The patient had significant pain relief at 3 months follow up.Pulsed radiofrequency lesioning may be a good treatment for chronic ilioinguinal neuropathy in cases refractory to conservative management.

Abstract

Functional MRI (fMRI) of the spinal cord is a noninvasive technique for obtaining information regarding spinal cord neuronal function. This article provides a brief overview of recent developments in spinal cord fMRI and outlines potential applications, as well as the limitations that must be overcome, for using spinal fMRI in the clinic. This technique is currently used for research purposes, but significant potential exists for spinal fMRI to become an important clinical tool.

Abstract

Complex regional pain syndrome (CRPS) remains a challenging condition to diagnose and treat. There are few large-scale, randomized trials of pharmacologic agents, and most published studies are small, uncontrolled, or presented only in abstract form at meetings. The most commonly used agents, such as anticonvulsants, antidepressants, and opiates, have been found to be useful for other neuropathic pain conditions in large-scale trials but have not been adequately studied in CRPS. Systemic steroids delivered by multiple routes continue to be used, with some good evidence for short-term administration. N-methyl-D-aspartate antagonists have recently gained in popularity, without evidence from well-controlled trials. Bisphosphonates have been well studied and offer promise. In addition, there has been interest in thalidomide; however, we are still awaiting well-controlled trials. This article presents an overview of the available data regarding pharmacologic therapies for CRPS. These agents should be used in conjunction with a comprehensive interdisciplinary approach aimed at functional restoration and improved quality of life.

Abstract

Although individual differences in fear and anxiety modulate the pain response and may even cause more suffering than the initiating physical stimulus, little is known about the neural systems mediating this relationship. The present study provided the first examination of the neural correlates of individual differences in the tendency to (1) feel anxious about the potentially negative implications of physical sensations, as measured by the anxiety sensitivity index (ASI), and (2) fear various types of physical pain, as indexed by the fear of pain questionnaire (FPQ). In separate sessions, participants completed these questionnaires and experienced alternating blocks of noxious thermal stimulation (45-50 degrees C) and neutral thermal stimulation (38 degrees C) during the collection of whole-brain fMRI data. Regression analyses demonstrated that during the experience of pain, ASI scores predicted activation of a medial prefrontal region associated with self-focused attention, whereas FPQ scores predicted activation of a ventral lateral frontal region associated with response regulation and anterior and posterior cingulate regions associated with monitoring and evaluation of affective responses. These functional relationships cannot be wholly explained by generalized anxiety (indexed by STAI-T scores), which did not significantly correlate with activation of any regions. The present findings may help clarify both the impact of individual differences in emotion on the neural correlates of pain, and the roles in anxiety, fear, and pain processing played by medial and orbitofrontal systems.

Abstract

If an individual can learn to directly control activation of localized regions within the brain, this approach might provide control over the neurophysiological mechanisms that mediate behavior and cognition and could potentially provide a different route for treating disease. Control over the endogenous pain modulatory system is a particularly important target because it could enable a unique mechanism for clinical control over pain. Here, we found that by using real-time functional MRI (rtfMRI) to guide training, subjects were able to learn to control activation in the rostral anterior cingulate cortex (rACC), a region putatively involved in pain perception and regulation. When subjects deliberately induced increases or decreases in rACC fMRI activation, there was a corresponding change in the perception of pain caused by an applied noxious thermal stimulus. Control experiments demonstrated that this effect was not observed after similar training conducted without rtfMRI information, or using rtfMRI information derived from a different brain region, or sham rtfMRI information derived previously from a different subject. Chronic pain patients were also trained to control activation in rACC and reported decreases in the ongoing level of chronic pain after training. These findings show that individuals can gain voluntary control over activation in a specific brain region given appropriate training, that voluntary control over activation in rACC leads to control over pain perception, and that these effects were powerful enough to impact severe, chronic clinical pain.

Abstract

Sophisticated regional anesthesia techniques have experienced substantial growth throughout the past 5 years for acute and chronic pain management. The recognition that regional anesthesia leads to superior postoperative outcomes in acute pain management and to an increased understanding of the pathogenesis of chronic pain has led to increased use of continuous peripheral nerve catheters. Furthermore, the availability of new equipment and techniques specifically designed to facilitate effective catheter placement has increased interest and adoption of peripheral nerve catheters to manage painful conditions. This has become particularly relevant as the scope of ambulatory surgery continues to grow. To maximize success rates with continuous peripheral nerve catheters, clinicians must be intimately aware of the pertinent regional anatomy and technical issues surrounding placement and maintenance of continuous nerve blockade. The recent development of outpatient infusion systems and novel anesthetics has been exciting and is likely to lead to an increase in the use of continuous peripheral catheter techniques. The consistent recognition that these techniques dramatically increase patient satisfaction should dictate an increasing presence in the field of pain management throughout the next several years.

Abstract

Understanding one's own and other individual's emotional states is essential for maintaining emotional equilibrium and strong social bonds. Although the neural substrates supporting ref lection upon one's own feelings have been investigated, no studies have directly examined attributions about the internal emotional states of others to determine whether common or distinct neural systems support these abilities. The present study sought to directly compare brain regions involved in judging one's own, as compared to another individual's, emotional state. Thirteen participants viewed mixed valence blocks of photos drawn from the International Affective Picture System while whole-brain fMRI data were collected. Preblock cues instructed participants to evaluate either their emotional response to each photo, the emotional state of the central figure in each photo, or (in a baseline condition) whether the photo was taken indoors or outdoors. Contrasts indicated (1) that both self and other judgments activated the medial prefrontal cortex (MPFC), the superior temporal gyrus, and the posterior cingulate/precuneus, (2) that self judgments selectively activated subregions of the MPFC and the left temporal cortex, whereas (3) other judgments selectively activated the left lateral prefrontal cortex (including Broca's area) and the medial occipital cortex. These results suggest (1) that self and other evaluation of emotion rely on a network of common mechanisms centered on the MPFC, which has been hypothesized to support mental state attributions in general, and (2) that medial and lateral PFC regions selectively recruited by self or other judgments may be involved in attention to, and elaboration of, internally as opposed to externally generated information.

Abstract

Pain remains a serious health care problem affecting millions of individuals, costing billions of dollars, and causing an immeasurable amount of human suffering. In designing improved therapies, there is still much to learn about peripheral nociceptor, nerves, and the spinal cord, and brain stem modulatory systems. Nevertheless, it is the brain that presents us with an incredible opportunity to understand the experience we call pain. Functional neuroimaging is helping to unlock the secrets of the sensory and emotional components of pain and its autonomic responses. These techniques are helping us to understand that pain is not a static disease with the pathologic findings localized to the periphery but is instead a highly plastic condition affecting multiple central neural systems. Functional neuroimaging is transforming our understanding of the neurobiology of pain and will be instrumental in helping us to design more rational treatments ultimately aimed at reducing the impact of pain on our patients. It is opening windows into the function of the brain that were previously closed.

Abstract

The study and treatment of clinical pain has historically identified particular pain syndromes and linked their etiology with disease factors. Missing in this approach is consideration of the mechanisms accounting for the pain that is experienced by the patient. The recent increase in our understanding of how peripheral and central mechanisms contribute to the perception of pain, including the identified role of prostaglandins, has led to a shift in treatment strategy to directly target these mechanisms. This article provides a brief overview of pain mechanisms, focusing on inflammatory pain, and discusses the role of cyclooxygenase (COX)-2 inhibitors as analgesic agents.

Abstract

The authors performed sympathetic nerve blockades in seven patients with peripheral ischemia and possible autonomic dysfunction. Magnetic resonance (MR) imaging was used to guide needle placement, to monitor distribution of injected agents, and to measure increases in blood flow, which were as much as 10-fold. MR imaging can provide both procedural imaging guidance and measurement of efficacy for sympathetic nerve blocks.

Abstract

To investigate if the use of a new double lumen i.v. set (DLIS) decreases the incidence of propofol injection pain compared with single lumen i.v. set (SLIS) administration.Prospective, randomized, double-blinded study.Operating rooms in a university hospital.50 adult ASA physical status I and II patients of both genders undergoing general anesthesia for elective surgery.Patients were injected with propofol either through a DLIS or a SLIS.Three different pain indices were recorded to be present or absent: (1) verbal report of pain during propofol injection (2) grimacing during propofol injection, and (3) recall of injection pain in the recovery room. When the DLIS was used, the incidence of verbal pain, grimacing during propofol injection, and recall of pain during recovery were lowered significantly by 53%, 46%, and 52%, respectively (chi square analysis of contingency table with Yates correction, p < 0.05).The DLIS significantly reduced the incidence of propofol injection pain compared with SLIS. Further studies are indicated to evaluate the cost-effectiveness of this device.

Abstract

Delivery of radiofrequency (RF) energy from the distal tip of electrophysiology catheters produces lesions that may be too small to ablate arrhythmogenic sites during a single application of RF energy. To produce larger lesions, we delivered RF energy via a quadripolar catheter in which all four electrodes were connected in unipolar fashion. The catheter (Webster Labs) had a 4-mm tip, 2-mm ring electrodes, and 2-mm interelectrode distance. Lesion size was compared using RF energy delivered in a multipolar configuration with that delivered only to the distal tip using fresh bovine ventricular tissue. In vivo, RF lesions were made in dogs using the distal tip as well as all four poles of the same catheter inserted percutaneously. RF energy was delivered using a constant voltage at a frequency of 400 kHz. Preliminary experiments were conducted to determine the maximum power deliverable without coagulation using each electrode configuration. The use of simultaneous multipolar RF ablation produced significantly larger lesions both in vitro and in vivo. The length of the lesion was increased by a factor of approximately 2 in both the in vitro and in vivo experiments. There was a trend toward an increasing depth of the lesion by simultaneously applying RF energy to all four electrodes. Lesion width was significantly increased in the in vivo studies. We concluded that simultaneous multipolar delivery of RF energy produces larger lesions than can be obtained with delivery of RF energy to the distal tip alone. This technique may offer a means of increasing lesion size, leading to a decrease in the number of applications of RF energy necessary for ablation of arrhythmias.

Abstract

During radiofrequency (RF) catheter ablation of arrhythmias, temperatures that approach 100 degrees C cause a coagulum to form on the ablation electrode that results in an increase in electrical impedance and prevents further energy delivery. Since gold has nearly four times the thermal conductivity as platinum, the metal commonly used, it was postulated that gold tip electrodes could deliver more power and produce deeper lesions because of its greater heat dissipation from the electrode-tissue interface to the circulating blood. To test this hypothesis, RF energy was applied to fresh bovine ventricular myocardium using 6 French catheters with 2-mm long distal electrodes made from gold or platinum. Similar studies were also conducted using 7 French catheters with 4-mm long distal electrodes. Maximum lesion depth was defined as that produced with the level of energy just below that causing an impedance rise. A maximum lesion depth of 6.2 +/- 0.7 mm (mean +/- SD) was obtained with the gold 2-mm electrode and 4.7 +/- 0.5 mm with the platinum electrode (P = 0.003). The 4-mm gold electrode produced a maximum lesion depth of 7.2 +/- 1.4 mm, while a catheter with a 4-mm platinum electrode caused a maximum lesion depth of 5.8 +/- 0.7 mm (P = 0.05). We conclude that deeper lesions should be able to be made when RF energy is delivered to a gold rather than platinum tip electrode.